Late and postmagmatic alterations in the tin-bearing batholith of Ricobayo (Iberian Massif, NW Spain)

The deuteric alteration processes undergone by the granites of the Ricobayo Batholith were: microclinization, chloritization, albitization, muscovitization, tourmalinization and garnetization. These processes must be interpreted in a dynamic context so that the different reactions that take place are the consequence of a successive interaction between rock and fluids. The physicochemical conditions deduced from these fluids are: temperature lower than 600 OC, pressure between 1.5 and 1 Kb, fugacity of oxygen between 10-25 and 10-35 bars, fugacity of sulphur lower than 10-l5 bars, the composition was kept stable and their log (a(K+)/a(Ht)) and log (a(Na+)/a(H+)) varied between 3.8 and 3.2 and between 3.5 and 4.6, respectively, and the pH of the fluids was higher than 5 during the microclinization, muscovitization and tourmalinization, and lower during chloritization and albitization. The deposition of cassiterite occurs with pH episodes that exceed 5.

Stepwise emergence of azole, echinocandin and amphotericin B multidrug resistance in vivo in Candida albicans orchestrated by multiple genetic alterations.

OBJECTIVES: The objective of this study was to characterize the underlying molecular mechanisms in consecutive clinical Candida albicans isolates from a single patient displaying stepwise-acquired multidrug resistance. METHODS: Nine clinical isolates (P-1 to P-9) were susceptibility tested by EUCAST EDef 7.2 and Etest. P-4, P-5, P-7, P-8 and P-9 were available for further studies. Relatedness was evaluated by MLST. Additional genes were analysed by sequencing (including FKS1, ERG11, ERG2 and TAC1) and gene expression by quantitative PCR (CDR1, CDR2 and ERG11). UV-spectrophotometry and GC-MS were used for sterol analyses. In vivo virulence was determined in the insect model Galleria mellonella and evaluated by log-rank Mantel-Cox tests. RESULTS: P-1 + P-2 were susceptible, P-3 + P-4 fluconazole resistant, P-5 pan-azole resistant, P-6 + P-7 pan-azole and echinocandin resistant and P-8 + P-9 MDR. MLST supported genetic relatedness among clinical isolates. P-4 harboured four changes in Erg11 (E266D, G307S, G450E and V488I), increased expression of ERG11 and CDR2 and a change in Tac1 (R688Q). P-5, P-7, P-8 and P-9 had an additional change in Erg11 (A61E), increased expression of CDR1, CDR2 and ERG11 (except for P-7) and a different amino acid change in Tac1 (R673L). Echinocandin-resistant isolates harboured the Fks1 S645P alteration. Polyene-resistant P-8 + P-9 lacked ergosterol and harboured a frameshift mutation in ERG2 (F105SfsX23). Virulence was attenuated (but equivalent) in the clinical isolates, but higher than in the azole- and echinocandin-resistant unrelated control strain. CONCLUSIONS: C. albicans demonstrates a diverse capacity to adapt to antifungal exposure. Potentially novel resistance-inducing mutations in TAC1, ERG11 and ERG2 require independent validation.

Phylogenetic relationships of Apodemus Kaup, 1829 (Rodentia: Muridae) species in the Eastern Mediterranean inferred from mitochondrial DNA, with emphasis on iranian species

Wood mice of the genus Apodemus are widely distributed in Eurasia, with the Eastern Mediterranean being considered as a hotspot. Indeed, numerous species have been documented in Iran, including A. witherbyi, A. hyrcanicus, A. uralensis, A. avicennicus, A. hermonensis, and A. arianus. In this study, 129 specimens were collected from different Iranian localities and two specimens from Afghanistan. The animals were identified taxonomically and their phylogenetic relationships were investigated using cytochrome b mitochondrial DNA sequences. Five species of the genus Apodemus were identified in Iran, including A. hyrcanicus, A. witherbyi, A. cf. ponticus, A. uralensis, and A. mystacinus, beside, A. pallipes from Afghanistan. This study found no evidence of A. flavicollis or A. sylvaticus in Iran, despite their occurrence in Turkey, shedding doubt on the status of A. flavicollis in Iran, Asia Minor, and the Levant. Phylogenetic analyses imply that A. witherbyi has priority over A. avicennicus, A. hermonensis, and A. iconicus. Estimation of the divergence time for these taxa suggests a separation at around 7.2 Ma for the subgenera Karstomys (including A. mystacinus and A. epimelas) and Sylvaemus (including A. flavicollis, A. sylvaticus, A. uralensis, A. pallipes, A. hyrcanicus, A. witherbyi, and A. cf. ponticus). Within the subgenus Karstomys, the divergence times for A. mystacinus and A. epimelas were between 3.0 and 6.1 Ma, and divergence times within the subgenus Sylvaemus were between 5.2 and 6.9 Ma for A. witherbyi and other species in this subgenus. It is postulated that vicariance events including the uplifting of the Zagros Mountains and Anatolian Plateau in the middle Miocene and climate oscillations during the Messinian Salinity Crisis besides formation of the Hyrcanian tertiary forests during the Neogene probably played substantial roles in the radiation and distribution of the genus Apodemus in the Eastern Mediterranean.

Skeletal Muscle Mitochondrial Function and Fatigability in Older Adults.

BACKGROUND: Fatigability increases while the capacity for mitochondrial energy production tends to decrease significantly with age. Thus, diminished mitochondrial function may contribute to higher levels of fatigability in older adults. METHODS: The relationship between fatigability and skeletal muscle mitochondrial function was examined in 30 participants aged 78.5 ± 5.0 years (47% female, 93% white), with a body mass index of 25.9 ± 2.7 kg/m(2) and usual gait-speed of 1.2 ± 0.2 m/s. Fatigability was defined using rating of perceived exertion (6-20 point Borg scale) after a 5-minute treadmill walk at 0.72 m/s. Phosphocreatine recovery in the quadriceps was measured using (31)P magnetic resonance spectroscopy and images of the quadriceps were captured to calculate quadriceps volume. ATPmax (mM ATP/s) and oxidative capacity of the quadriceps (ATPmax·Quadriceps volume) were calculated. Peak aerobic capacity (VO2peak) was measured using a modified Balke protocol. RESULTS: ATPmax·Quadriceps volume was associated with VO2peak and was 162.61mM ATP·mL/s lower (p = .03) in those with high (rating of perceived exertion ≥10) versus low (rating of perceived exertion ≤9) fatigability. Participants with high fatigability required a significantly higher proportion of VO2peak to walk at 0.72 m/s compared with those with low fatigability (58.7 ± 19.4% vs 44.9 ± 13.2%, p < .05). After adjustment for age and sex, higher ATPmax was associated with lower odds of having high fatigability (odds ratio: 0.34, 95% CI: 0.11-1.01, p = .05). CONCLUSIONS: Lower capacity for oxidative phosphorylation in the quadriceps, perhaps by contributing to lower VO2peak, is associated with higher fatigability in older adults.

The Armc10/SVH gene: Genome context, regulation of mitochondrial dynamics and protection against Aβ-induced mitochondrial fragmentation

Mitochondrial function and dynamics are essential for neurotransmission, neural function and neuronal viability. Recently, we showed that the eutherian-specific Armcx gene cluster (Armcx1-6 genes), located in the X chromosome, encodes for a new family of proteins that localise to mitochondria, regulating mitochondrial trafficking. The Armcx gene cluster evolved by retrotransposition of the Armc10 gene mRNA, which is present in all vertebrates and is considered to be the ancestor gene. Here we investigate the genomic organisation, mitochondrial functions and putative neuroprotective role of the Armc10 ancestor gene. The genomic context of the Armc10 locus shows considerable syntenic conservation among vertebrates, and sequence comparisons and CHIP-data suggest the presence of at least three conserved enhancers. We also show that the Armc10 protein localises to mitochondria and that it is highly expressed in the brain. Furthermore, we show that Armc10 levels regulate mitochondrial trafficking in neurons, but not mitochondrial aggregation, by controlling the number of moving mitochondria. We further demonstrate that the Armc10 protein interacts with the KIF5/Miro1-2/Trak2 trafficking complex. Finally, we show that overexpression of Armc10 in neurons prevents A beta-induced mitochondrial fission and neuronal death. Our data suggest both conserved and differential roles of the Armc10/Armcx gene family in regulating mitochondrial dynamics in neurons, and underscore a protective effect of the Armc10 gene against A beta-induced toxicity. Overall, our findings support a further degree of regulation of mitochondrial dynamics in the brain of more evolved mammals.

The Armc10/SVH gene: Genome context, regulation of mitochondrial dynamics and protection against Aβ-induced mitochondrial fragmentation

Mitochondrial function and dynamics are essential for neurotransmission, neural function and neuronal viability. Recently, we showed that the eutherian-specific Armcx gene cluster (Armcx1-6 genes), located in the X chromosome, encodes for a new family of proteins that localise to mitochondria, regulating mitochondrial trafficking. The Armcx gene cluster evolved by retrotransposition of the Armc10 gene mRNA, which is present in all vertebrates and is considered to be the ancestor gene. Here we investigate the genomic organisation, mitochondrial functions and putative neuroprotective role of the Armc10 ancestor gene. The genomic context of the Armc10 locus shows considerable syntenic conservation among vertebrates, and sequence comparisons and CHIP-data suggest the presence of at least three conserved enhancers. We also show that the Armc10 protein localises to mitochondria and that it is highly expressed in the brain. Furthermore, we show that Armc10 levels regulate mitochondrial trafficking in neurons, but not mitochondrial aggregation, by controlling the number of moving mitochondria. We further demonstrate that the Armc10 protein interacts with the KIF5/Miro1-2/Trak2 trafficking complex. Finally, we show that overexpression of Armc10 in neurons prevents A beta-induced mitochondrial fission and neuronal death. Our data suggest both conserved and differential roles of the Armc10/Armcx gene family in regulating mitochondrial dynamics in neurons, and underscore a protective effect of the Armc10 gene against A beta-induced toxicity. Overall, our findings support a further degree of regulation of mitochondrial dynamics in the brain of more evolved mammals.

Comparison of Four Sections for Analyzing Running Mechanics Alterations During Repeated Treadmill Sprints.

We compared different approaches to analyze running mechanics alterations during repeated treadmill sprints. Thirteen active male athletes performed five 5-second sprints with 25 seconds of recovery on an instrumented treadmill. This approach allowed continuous measurement of running kinetics/kinematics and calculation of vertical and leg stiffness variables that were subsequently averaged over 3 distinct sections of the 5-second sprint (steps 2-5, 7-10, and 12-15) and for all steps (steps 2-15). Independently from the analyzed section, propulsive power and step frequency decreased with fatigue, while contact time and step length increased (P < .05). Except for step frequency, all mechanical variables varied (P < .05) across sprint sections. The only parameters that highly depend on running velocity (propulsive power and vertical stiffness) showed a significant interaction (P < .05) between the analyzed sections, with smaller magnitude of fatigue-induced change observed for steps 2-5. Considering all steps or only a few steps during early, middle, or late phases of 5-second sprints provides similar mechanical outcomes during repeated treadmill sprinting, although acceleration induces noticeable differences between the sections studied. Furthermore, quantifying mechanical alterations from the early acceleration phase may not be readily detectable, and is not recommended.

Reversible mitochondrial respiratory chain impairment during symptomatic hyperlactatemia associated with antiretroviral therapy

Direct evidence confirming the hypothesis that a dysfunction of the mitochondrial respiratory chain (MRC) underlies the pathogenesis of hyperlactatemia associated with highly active antiretroviral therapy (HAART) is scarce. We studied mitochondrial DNA (mtDNA) content and MRC function in the skeletal muscle of an HIV-infected patient during an episode of symptomatic hyperlactatemia. Skeletal muscle biopsy was performed during the episode when the patient was symptomatic and 3 months later when the patient was clinically recovered. Assessment of mitochondria was performed using histological, polarographic, spectrophotometrical, and Southern blot and real time PCR DNA quantification methods. The histological study disclosed extensive mitochondrial impairment in the form of ragged-red fibers or equivalents on oxidative reactions. These findings were associated with an increase in mitochondrial content and a decrease in both mitochondrial respiratory capacity and MRC enzyme activities. Mitochondrial DNA content declined to 53% of control values. Mitochondrial abnormalities had almost disappeared later when the patient became asymptomatic. Our findings support the hypothesis that MRC dysfunction stands at the basis of HAART-related hyperlactatemia.

Reversible mitochondrial respiratory chain impairment during symptomatic hyperlactatemia associated with antiretroviral therapy

Direct evidence confirming the hypothesis that a dysfunction of the mitochondrial respiratory chain (MRC) underlies the pathogenesis of hyperlactatemia associated with highly active antiretroviral therapy (HAART) is scarce. We studied mitochondrial DNA (mtDNA) content and MRC function in the skeletal muscle of an HIV-infected patient during an episode of symptomatic hyperlactatemia. Skeletal muscle biopsy was performed during the episode when the patient was symptomatic and 3 months later when the patient was clinically recovered. Assessment of mitochondria was performed using histological, polarographic, spectrophotometrical, and Southern blot and real time PCR DNA quantification methods. The histological study disclosed extensive mitochondrial impairment in the form of ragged-red fibers or equivalents on oxidative reactions. These findings were associated with an increase in mitochondrial content and a decrease in both mitochondrial respiratory capacity and MRC enzyme activities. Mitochondrial DNA content declined to 53% of control values. Mitochondrial abnormalities had almost disappeared later when the patient became asymptomatic. Our findings support the hypothesis that MRC dysfunction stands at the basis of HAART-related hyperlactatemia.

Drug-induced mitochondrial dysfunction and cardiotoxicity.

Mitochondria has an essential role in myocardial tissue homeostasis; thus deterioration in mitochondrial function eventually leads to cardiomyocyte and endothelial cell death and consequent cardiovascular dysfunction. Several chemical compounds and drugs have been known to directly or indirectly modulate cardiac mitochondrial function, which can account both for the toxicological and pharmacological properties of these substances. In many cases, toxicity problems appear only in the presence of additional cardiovascular disease conditions or develop months/years following the exposure, making the diagnosis difficult. Cardiotoxic agents affecting mitochondria include several widely used anticancer drugs [anthracyclines (Doxorubicin/Adriamycin), cisplatin, trastuzumab (Herceptin), arsenic trioxide (Trisenox), mitoxantrone (Novantrone), imatinib (Gleevec), bevacizumab (Avastin), sunitinib (Sutent), and sorafenib (Nevaxar)], antiviral compound azidothymidine (AZT, Zidovudine) and several oral antidiabetics [e.g., rosiglitazone (Avandia)]. Illicit drugs such as alcohol, cocaine, methamphetamine, ecstasy, and synthetic cannabinoids (spice, K2) may also induce mitochondria-related cardiotoxicity. Mitochondrial toxicity develops due to various mechanisms involving interference with the mitochondrial respiratory chain (e.g., uncoupling) or inhibition of the important mitochondrial enzymes (oxidative phosphorylation, Szent-Györgyi-Krebs cycle, mitochondrial DNA replication, ADP/ATP translocator). The final phase of mitochondrial dysfunction induces loss of mitochondrial membrane potential and an increase in mitochondrial oxidative/nitrative stress, eventually culminating into cell death. This review aims to discuss the mechanisms of mitochondrion-mediated cardiotoxicity of commonly used drugs and some potential cardioprotective strategies to prevent these toxicities.

Nrf2 Activation Promotes Keratinocyte Survival during Early Skin Carcinogenesis via Metabolic Alterations.

Pharmacologic activation of the transcription factor NRF2 has been suggested to offer a strategy for cancer prevention. In this study, we present evidence from murine tumorigenesis experiments suggesting there may be limitations to this possibility, based on tumorigenic effects of Nrf2 in murine keratinocytes that have not been described previously. In this setting, Nrf2 expression conferred metabolic alterations in keratinocytes that were protumorigenic in nature, affecting enzymes involved in glutathione biosynthesis or in the oxidative pentose phosphate pathway and other NADPH-producing enzymes. Under stress conditions, coordinate increases in NADPH, purine, and glutathione levels promoted the survival of keratinocytes harboring oncogenic mutations, thereby promoting tumor development. The protumorigenic activity of Nrf2 in keratinocytes was particularly significant in a mouse model of skin tumorigenesis that did not rely upon chemical carcinogenesis. In exploring the clinical relevance of our findings, we confirm that NRF2 and protumorigenic NRF2 target genes were activated in some actinic keratoses, the major precancerous lesion in human skin. Overall, our results reveal an unexpected tumor-promoting activity of activated NRF2 during early phases of skin tumorigenesis. Cancer Res; 75(22); 4817-29. ©2015 AACR.

Connectivity and tissue microstructural alterations in right and left temporal lobe epilepsy revealed by diffusion spectrum imaging.

Focal epilepsy is increasingly recognized as the result of an altered brain network, both on the structural and functional levels and the characterization of these widespread brain alterations is crucial for our understanding of the clinical manifestation of seizure and cognitive deficits as well as for the management of candidates to epilepsy surgery. Tractography based on Diffusion Tensor Imaging allows non-invasive mapping of white matter tracts in vivo. Recently, diffusion spectrum imaging (DSI), based on an increased number of diffusion directions and intensities, has improved the sensitivity of tractography, notably with respect to the problem of fiber crossing and recent developments allow acquisition times compatible with clinical application. We used DSI and parcellation of the gray matter in regions of interest to build whole-brain connectivity matrices describing the mutual connections between cortical and subcortical regions in patients with focal epilepsy and healthy controls. In addition, the high angular and radial resolution of DSI allowed us to evaluate also some of the biophysical compartment models, to better understand the cause of the changes in diffusion anisotropy. Global connectivity, hub architecture and regional connectivity patterns were altered in TLE patients and showed different characteristics in RTLE vs LTLE with stronger abnormalities in RTLE. The microstructural analysis suggested that disturbed axonal density contributed more than fiber orientation to the connectivity changes affecting the temporal lobes whereas fiber orientation changes were more involved in extratemporal lobe changes. Our study provides further structural evidence that RTLE and LTLE are not symmetrical entities and DSI-based imaging could help investigate the microstructural correlate of these imaging abnormalities.

Running mechanical alterations during repeated treadmill sprints in hot versus hypoxic environments : a pilot study.

We determined if performance and mechanical running alterations during repeated treadmill sprinting differ between severely hot and hypoxic environments. Six male recreational sportsmen (team- and racket-sport background) performed five 5-s sprints with 25-s recovery on an instrumented treadmill, allowing the continuous (step-by-step) measurement of running kinetics/kinematics and spring-mass characteristics. These were randomly conducted in control (CON; 25°C/45% RH, inspired fraction of oxygen = 20.9%), hot (HOT; 38°C/21% RH, inspired fraction of oxygen = 20.9%; end-exercise core temperature: ~38.6°C) and normobaric hypoxic (HYP, 25°C/45% RH, inspired fraction of oxygen = 13.3%/simulated altitude of ~3600 m; end-exercise pulse oxygen saturation: ~84%) environments. Running distance was lower (P < 0.05) in HOT compared to CON and HYP for the first sprint but larger (P < 0.05) sprint decrement score occurred in HYP versus HOT and CON. Compared to CON, the cumulated distance covered over the five sprints was lower (P < 0.01) in HYP but not in HOT. Irrespective of the environmental condition, significant changes occurred from the first to the fifth sprint repetitions (all three conditions compounded) in selected running kinetics (mean horizontal forces, P < 0.01) or kinematics (contact and swing times, both P < 0.001; step frequency, P < 0.001) and spring-mass characteristics (vertical stiffness, P < 0.001; leg stiffness, P < 0.01). No significant interaction between sprint number and condition was found for any mechanical data. Preliminary evidence indicates that repeated-sprint ability is more impaired in hypoxia than in a hot environment, when compared to a control condition. However, as sprints are repeated, mechanical alterations appear not to be exacerbated in severe (heat, hypoxia) environmental conditions.

Abdominal alterations in disseminated paracoccidioidomycosis: computed tomography findings

Objective:To evaluate the incidence and spectrum of abdominal computed tomography imaging findings in patients with paracoccidioidomycosis.Materials and Methods:Retrospective analysis of abdominal computed tomography images of 26 patients with disseminated paracoccidioidomycosis.Results:Abnormal abdominal tomographic findings were observed in 18 patients (69.2%), while no significant finding was observed in the other 8 (30.8%) patients.Conclusion:Computed tomography has demonstrated to play a relevant role in the screening and detection of abdominal abnormalities in patients with disseminated paracoccidioidomycosis.

Sensibility and taste alterations after impacted lower third molar extractions. A prospective cohort study

Objectives: To determine the incidence, severity and duration of lingual tactile and gustatory function impairments after lower third molar removal. Study Design: Prospective cohort study with intra-subject measures of 16 patients undergoing lower third molar extractions. Sensibility and gustatory functions were evaluated in each subject preoperatively, one week and one month after the extraction, using Semmes-Weinstein monofilaments and 5 different concentrations of NaCl, respectively. Additionally, all patients filled a questionnaire to assess subjective perceptions. Results: Although patients did not perceive any sensibility impairments, a statistically significant decrease was detected when Semmes-Weinstein monofilaments. This alteration was present at one week after the surgical procedure and fully recovered one month after the extraction. There were no variations regarding the gustatory function. Conclusions: Lower third molar removal under local anesthesia may cause light lingual sensibility impairment. Most of these alterations remain undetected to patients. These lingual nerve injuries are present one week after the extraction and recover one month after surgery. The taste seems to remain unaffected after these procedures.