Mitochondrial fusion and fission is a dynamic process critical for the maintenance of mitochondrial function and cell viability. During excitotoxicity neuronal mitochondria are fragmented, but the ...mechanism underlying this process is poorly understood. Here, we show that Mfn2 is the only member of the mitochondrial fusion/fission machinery whose expression is reduced in in vitro and in vivo models of excitotoxicity. Whereas in cortical primary cultures, Drp1 recruitment to mitochondria plays a primordial role in mitochondrial fragmentation in an early phase that can be reversed once the insult has ceased, Mfn2 downregulation intervenes in a delayed mitochondrial fragmentation phase that progresses even when the insult has ceased. Downregulation of Mfn2 causes mitochondrial dysfunction, altered calcium homeostasis, and enhanced Bax translocation to mitochondria, resulting in delayed neuronal death. We found that transcription factor MEF2 regulates basal Mfn2 expression in neurons and that excitotoxicity‐dependent degradation of MEF2 causes Mfn2 downregulation. Thus, Mfn2 reduction is a late event in excitotoxicity and its targeting may help to reduce excitotoxic damage and increase the currently short therapeutic window in stroke.
Synopsis
Excitotoxicity leads to mitochondrial fragmentation, altered calcium homeostasis and neuronal death in two phases: a reversible Drp1‐dependent one, followed by the irreversible degradation of MEF2, causing reduced Mfn2 transcription and Bax translocation to mitochondria.
MEF2 regulates Mfn2 basal transcription in neurons.
MEF2 degradation in excitotoxicity causes Mfn2 downregulation.
Reduced Mfn2 expression causes mitochondrial dysfunction and altered calcium homeostasis.
Mfn2 downregulation in excitotoxicity participates in delayed cell death by facilitating Bax recruitment to mitochondria.
Excitotoxicity leads to mitochondrial fragmentation, altered calcium homeostasis and neuronal death in two phases: a reversible Drp1‐dependent one, followed by the irreversible degradation of MEF2, causing reduced Mfn2 transcription and Bax translocation to mitochondria.
We study the structure and tectonics of the collision zone between the Nazca Ridge (NR) and the Peruvian margin constrained by seismic, gravimetric, bathymetric, and natural seismological data. The ...NR was formed in an on‐ridge setting, and it is characterized by a smooth and broad shallow seafloor (swell) with an estimated buoyancy flux of ~7 Mg/s. The seismic results show that the NR hosts an oceanic lower crust 10–14 km thick with velocities of 7.2–7.5 km/s suggesting intrusion of magmatic material from the hot spot plume to the oceanic plate. Our results show evidence for subduction erosion in the frontal part of the margin likely enhanced by the collision of the NR. The ridge‐trench collision zone correlates with the presence of a prominent normal scarp, a narrow continental slope, and (uplifted) shelf. In contrast, adjacent of the collision zone, the slope does not present a topographic scarp and the continental slope and shelf become wider and deeper. Geophysical and geodetic evidence indicate that the collision zone is characterized by low seismic coupling at the plate interface. This is consistent with vigorous subduction erosion enhanced by the subducting NR causing abrasion and increase of fluid pore pressure at the interplate contact. Furthermore, the NR has behaved as a barrier for rupture propagation of megathrust earthquakes (e.g., 1746 Mw 8.6 and 1942 Mw 8.1 events). In contrast, for moderate earthquakes (e.g., 1996 Mw 7.7 and 2011 Mw 6.9 events), the NR has behaved as a seismic asperity nucleating at depths >20 km.
Key Points
The Nazca Ridge hosts an overthickened lower crust (10–14 km) formed in an on‐ridge setting (hot spot plume near a spreading center)
The Nazca Ridge correlates with a prominent continental slope scarp bounded by a narrow and uplifted continental shelf
The Nazca Ridge has behaved as a seismic asperity for moderate earthquakes (e.g., 1996 Mw 7.7 and 2011 Mw 6.9) nucleating at depths >20 km
Glyphosate is a broad-spectrum and one of the most widely used herbicides in the world, which has led to its high environmental dissemination. In 2015, the International Agency for Research on Cancer ...stated that glyphosate was a probable human carcinogen. Since then, several studies have provided new data about the environmental exposure of glyphosate and its consequences on human health. Thus, the carcinogenic effects of glyphosate are still under debate. This work aimed to review glyphosate occurrence and exposure since 2015 up to date, considering studies associated with either environmental or occupational exposure and the epidemiological assessment of cancer risk in humans. These articles showed that herbicide residues were detectable in all spheres of the earth and studies on the population showed an increase in the concentration of glyphosate in biofluids, both in the general population and in the occupationally exposed population. However, the epidemiological studies under review provided limited evidence for the carcinogenicity of glyphosate, which was consistent with the International Agency for Research on Cancer classification as a probable carcinogen.
The B cell leukemia/lymphoma 2 (BCL-2) inhibitor venetoclax is effective in chronic lymphocytic leukemia (CLL); however, resistance may develop over time. Other lymphoid malignancies such as diffuse ...large B cell lymphoma (DLBCL) are frequently intrinsically resistant to venetoclax. Although genomic resistance mechanisms such as BCL2 mutations have been described, this probably only explains a subset of resistant cases. Using 2 complementary functional precision medicine techniques - BH3 profiling and high-throughput kinase activity mapping - we found that hyperphosphorylation of BCL-2 family proteins, including antiapoptotic myeloid leukemia 1 (MCL-1) and BCL-2 and proapoptotic BCL-2 agonist of cell death (BAD) and BCL-2 associated X, apoptosis regulator (BAX), underlies functional mechanisms of both intrinsic and acquired resistance to venetoclax in CLL and DLBCL. Additionally, we provide evidence that antiapoptotic BCL-2 family protein phosphorylation altered the apoptotic protein interactome, thereby changing the profile of functional dependence on these prosurvival proteins. Targeting BCL-2 family protein phosphorylation with phosphatase-activating drugs rewired these dependencies, thus restoring sensitivity to venetoclax in a panel of venetoclax-resistant lymphoid cell lines, a resistant mouse model, and in paired patient samples before venetoclax treatment and at the time of progression.
To describe the current epidemiology of bloodstream infection (BSI) in patients with cirrhosis; and to analyse predictors of 30-day mortality and risk factors for antibiotic resistance.
Cirrhotic ...patients developing a BSI episode were prospectively included at 19 centres in five countries from September 2014 to December 2015. The discrimination of mortality risk scores for 30-day mortality were compared by area under the receiver operator risk and Cox regression models. Risk factors for multidrug-resistant organisms (MDRO) were assessed with a logistic regression model.
We enrolled 312 patients. Gram-negative bacteria, Gram-positive bacteria and Candida spp. were the cause of BSI episodes in 53%, 47% and 7% of cases, respectively. The 30-day mortality rate was 25% and was best predicted by the Sequential Organ Failure Assessment (SOFA) and Chronic Liver Failure–SOFA (CLIF-SOFA) score. In a Cox regression model, delayed (>24 hours) antibiotic treatment (hazard ratio (HR) 7.58; 95% confidence interval (CI) 3.29–18.67; p < 0.001), inadequate empirical therapy (HR 3.14; 95% CI 1.93–5.12; p < 0.001) and CLIF-SOFA score (HR 1.35; 95% CI 1.28–1.43; p < 0.001) were independently associated with 30-day mortality. Independent risk factors for MDRO (31% of BSIs) were previous antimicrobial exposure (odds ratio (OR) 2.91; 95% CI 1.73–4.88; p < 0.001) and previous invasive procedures (OR 2.51; 95% CI 1.48–4.24; p 0.001), whereas spontaneous bacterial peritonitis as BSI source was associated with a lower odds of MDRO (OR 0.30; 95% CI 0.12–0.73; p 0.008).
MDRO account for nearly one-third of BSI in cirrhotic patients, often resulting in delayed or inadequate empirical antimicrobial therapy and increased mortality rates. Our data suggest that improved prevention and treatment strategies for MDRO are urgently needed in the liver cirrhosis patients.
Background
Urinary tract infection (UTI) is the most common infection in renal transplant patients, but it is necessary to determine the risk factors for bacterial UTI in recipients of other solid ...organ transplants (SOTs), as well as changes in etiology, clinical presentation, and prognosis.
Methods
In total, 4388 SOT recipients were monitored in 16 transplant centers belonging to the Spanish Network for Research on Infection in Transplantation (RESITRA). The frequency and characteristics of bacterial UTI in transplant patients were obtained prospectively from the cohort (September 2003 to February 2005).
Results
A total of 192 patients (4.4%) presented 249 episodes of bacterial UTI (0.23 episodes per 1000 transplantation days); 156 patients were kidney or kidney–pancreas transplant recipients, and 36 patients were liver, heart, and lung transplant recipients. The highest frequency was observed in renal transplants (7.3%). High frequency of cystitis versus pyelonephritis without related mortality was observed in both groups. The most frequent etiology was Escherichia coli (57.8%), with 25.7% producing extended‐spectrum β‐lactamase (ESBL). In all transplants but renal, most cases occurred in the first month after transplantation. Cases were uniformly distributed during the first 6 months after transplantation in renal recipients. Age (odds ratio OR per decade 1.1, 95% confidence interval CI 1.02–1.17), female gender (OR 1.74, 95% CI 1.42–2.13), and the need for immediate post‐transplant dialysis (OR 1.63, 95% CI 1.29–2.05) were independent variables associated with bacterial UTI in renal and kidney–pancreas recipients. The independent risk factors identified in non‐renal transplants were age (OR per decade 1.79, 95% CI 1.09–3.48), female gender (OR 1.7, 95% CI 1.43–2.49), and diabetes (OR 1.02, 95% CI 1.001–1.040).
Conclusions
UTI was frequent in renal transplants, but also not unusual in non‐renal transplants. Because E. coli continues to be the most frequent etiology, the emergence of ESBL‐producing strains has been identified as a new problem. In both populations, most cases were cystitis without related mortality. Although the first month after transplantation was a risk period in all transplants, cases were uniformly distributed during the first 6 months in renal transplants. Age and female gender were identified as risk factors for UTI in both populations. Other particular risk factors were the need for immediate post‐transplant dialysis in renal transplants and diabetes in non‐renal transplants.
Acetylcholine (ACh) is a neurotransmitter that regulates multiple functions in the nervous system, and emerging evidence indicates that it could play a role in cancer progression. However, this ...function is controversial. Previously, we showed that organophosphorus pesticides decreased the levels of the enzyme acetylcholinesterase in vivo, increasing ACh serum levels and the formation of tumors in the mammary glands of rats. Furthermore, we showed that ACh exposure in breast cancer cell lines induced overexpression of estrogen receptor alpha (ERα), a key protein described as the master regulator in breast cancer. Therefore, here, we hypothesize that ACh alters the ERα activity through a ligand-independent mechanism. The results here reveal that the physiological concentration of ACh leads to the release of Ca+2 and the activity of MAPK/ERK and PI3K/Akt pathways. These changes are associated with an induction of p-ERα and its recruitment to the nucleus. However, ACh fails to induce overexpression of estrogen-responsive genes, suggesting a different activation mechanism than that of 17ß-estradiol. Finally, ACh promotes the viability of breast cancer cell lines in an ERα-dependent manner and induces the overexpression of some EMT markers. In summary, our results show that ACh promotes breast cancer cell proliferation and ERα activity, possibly in a ligand-independent manner, suggesting its putative role in breast cancer progression.
MFN2 (mitofusin 2) is required for mitochondrial fusion and for mitochondria-endoplasmic reticulum interaction. Using myeloid-conditional KO mice models, we found that MFN2 but not MFN1 is a ...prerequisite for the adaptation of mitochondrial respiration to stress conditions as well as for the production of reactive oxygen species (ROS). The deficient ROS production in the absence of MFN2 impairs the induction of cytokines and nitric oxide, and is associated with dysfunctional autophagy, apoptosis, phagocytosis, and antigen processing. The lack of MFN2 in macrophages causes an impaired response in a model of non-septic inflammation in mice, as well as a failure in protection from Listeria, Mycobacterium tuberculosis or LPS endotoxemia. These results reveal an unexpected role of MFN2 to ROS production in macrophages affecting natural and acquired immunity and the immune response.
Use of cooled and frozen semen is becoming increasingly prevalent in the equine industry. However, these procedures cause harmful effects in the sperm cell resulting in reduced cell lifespan and ...fertility rates. Apoptosis and necrosis-related events are increased during semen cryopreservation. However, a third type of cell death, named autophagy, has not been studied during equine semen storage. Light chain (LC)3 protein is a key component of the autophagy pathway. Under autophagy activation, LC3-I is lipidated and converted to LC3-II. The ratio of LC3-II/LC3-I is widely used as a marker of autophagy activation. The main objective of this study was to investigate whether LC3 is processed during cooling, freezing and the stressful conditions associated with these technologies. A secondary objective was to determine if LC3 processing can be modulated and if that may improve the quality of cryopreserved semen. LC3 processing was studied by Western blot with a specific antibody that recognized both LC3-I and LC3-II. Viability was assessed by flow cytometry. Modulation of LC3-I to LC3-II was studied with known autophagy activators (STF-62247 and rapamycin) or inhibitors (chloroquine and 3-MA) used in somatic cells. The results showed that conversion of LC3-I to LC3-II increased significantly during cooling at 4°C, freezing/thawing and each of the stressful conditions tested (UV radiation, oxidative stress, osmotic stress and changes in temperature). STF-62247 and rapamycin increased the LC3-II/LC3-I ratio and decreased the viability of equine sperm, whereas chloroquine and 3-MA inhibited LC3 processing and maintained the percentage of viable cells after 2 h of incubation at 37°C. Finally, refrigeration at 4°C for 96 h and freezing at -196°C in the presence of chloroquine and 3-MA resulted in higher percentages of viable cells. In conclusion, results showed that an 'autophagy-like' mechanism may be involved in the regulation of sperm viability during equine semen cryopreservation. Modulation of autophagy during these reproductive technologies may result in an improvement of semen quality and therefore in higher fertility rates.
•Nine cement-sand-based admixtures with improved properties were characterized.•Different sands and advanced additives were used for the fluid mortars design.•Thermal and mechanical properties were ...assessed, including pipe-mortar bond strength.•Good ratios of thermal to mechanical performance were obtained.•Mortars were subjected to wet-dry cycles for durability assessment.
Nowadays, Ground Source Heat Pumps (GSHP) are achieving significant efficiencies, mostly because of the development of their electromechanical components. However, concepts such as the technical performance of the grouting materials deserve more profound analysis, as becoming essential in areas where good potential thermal performance of the GSHP and serious risks of groundwater contamination exist. In this paper, several fluid mortars with enhanced characteristics have been evaluated. Results show improved mechanical and thermal properties compared to conventional grouting materials. Likewise, mortars exhibited good performance after being subjected to durability treatment. For now, the cost of some mortars may constitute a barrier.
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