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Urinary tract infections are common. Here, we delineate a role of extracellular DNA trap (ET) formation in kidney antibacterial defense and determine mechanisms of their formation in the hyperosmotic environment of the kidney medulla. ET of granulocytic and monocytic origin were present in the kidneys of patients with pyelonephritis along with systemically elevated citrullinated histone levels. Inhibition of the transcription coregulatory, peptidylarginine deaminase 4 (PAD4), required for ET formation, prevented kidney ET formation and promoted pyelonephritis in mice. ETs predominantly accumulated in the kidney medulla. The role of medullary sodium chloride and urea concentrations in ET formation was then investigated. Medullary-range sodium chloride, but not urea, dose-, time- and PAD4-dependently induced ET formation even in the absence of other stimuli. Moderately elevated sodium chloride promoted myeloid cell apoptosis. Sodium gluconate also promoted cell death, proposing a role for sodium ions in this process. Sodium chloride induced myeloid cell calcium influx. Calcium ion-free media or -chelation reduced sodium chloride-induced apoptosis and ET formation while bacterial lipopolysaccharide amplified it. Autologous serum improved bacterial killing in the presence of sodium chloride-induced ET. Depletion of the kidney sodium chloride gradient by loop diuretic therapy diminished kidney medullary ET formation and increased pyelonephritis severity. Thus, our data demonstrate that ETs may protect the kidney against ascending uropathogenic E. coli and delineate kidney medullary range sodium chloride concentrations as novel inducers of programmed myeloid cell death.
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Armadilhas Extracelulares , Pielonefrite , Camundongos , Animais , Cloreto de Sódio/farmacologia , Neutrófilos , Monócitos , Cálcio , Escherichia coli , Rim , Pielonefrite/tratamento farmacológico , DNA , UreiaRESUMO
BACKGROUND AND PURPOSE: To investigate severe autoimmune encephalitis (AE) in the intensive care unit (ICU) with regard to standard treatment in responsive patients and additional escalation therapies for treatment-refractory cases. METHODS: This retrospective, single-center study analyzed medical records of ICU-dependent AE patients for clinical characteristics, treatments, prognostic factors, and neurological outcome as quantified by modified Rankin Scale (mRS) and Clinical Assessment Scale for Autoimmune Encephalitis (CASE). RESULTS: From 40 enrolled patients (median age = 52 years; range = 16-89 years) with AE mediated by neuronal surface antibodies (nsAb; 90%) and AE with onconeuronal antibodies (10%), 98% received first-line therapy. Of those, 62% obtained additional second-line therapy, and 33% received escalation therapy with bortezomib and/or daratumumab. Good neurological outcome, defined as mRS = 0-2, was observed in 47% of AE with nsAb (CASE = 5), 77% of anti-N-methyl D-aspartate receptor encephalitis patients (CASE = 1), whereas AE patients with onconeuronal antibodies had the poorest outcome (mRS = 6, 100%). Treatment-refractory AE patients with nsAb requiring escalation therapy achieved similarly good recovery (mRS = 0-2, 39%, CASE = 3) as patients improving without (mRS = 0-2, 54%, CASE = 4), although they presented a higher disease severity at disease maximum (mRS = 5 100% versus 68%, CASE = 24 versus 17; p = 0.0036), had longer ICU stays (97 versus 23 days; p = 0.0002), and a higher survival propability during follow-up (p = 0.0203). Prognostic factors for good recovery were younger age (p = 0.025) and lack of preexisting comorbidities (p = 0.011). CONCLUSIONS: Our findings suggest that treatment-refractory AE patients with nsAb in the ICU can reach similarly good outcomes after plasma cell-depleting escalation therapy as patients already responding to standard first- and/or second-line therapies.
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Encefalite Antirreceptor de N-Metil-D-Aspartato , Plasmócitos , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Encefalite Antirreceptor de N-Metil-D-Aspartato/terapia , Unidades de Terapia IntensivaRESUMO
The Rho GTPase Miro1, located at the mitochondrial outer membrane is known to properly distribute mitochondria to synapses, aid calcium buffering and initiate PINK1-Parkin mediated mitophagy. Several heterozygous RHOT1/Miro1 variants were identified in sporadic Parkinson's disease patients. Miro1 R272Q is located within a calcium binding domain, but the functional outcome of this point mutation and its contribution to the development of disease are unclear. To address this, we introduced a heterozygous RHOT1/Miro1 R272Q point mutation in healthy induced pluripotent stem cells. In dopaminergic neurons, Miro1 R272Q does not affect Miro1 protein levels, CCCP-induced mitophagy, nor mitochondrial movement yet causes the fragmentation of mitochondria with reduction of cristae and ATP5A. Inhibition of the mitochondrial calcium uniporter phenocopied Miro1 R272Q cytosolic calcium response to Thapsigargin in active neurons, a similar effect was observed during the calcium buffering phase in Miro1 knockdown neuroblastoma cells. Altered mitochondrial calcium regulation is associated with reduced mitochondrial respiration and reduced catecholamine neurotransmitter uptake. Synaptic changes are not coupled to dopamine distribution or dopamine transporters but are linked to Miro1 R272Q-related calcium handling via the mitochondria concomitant with defective dopamine regulation at the mitochondrial surface by monoamine oxidase. We conclude that the Miro1 R272Q heterozygous point mutation dampens mitochondrial-calcium regulation and mitochondrial capacity via events at the outer membrane that are sufficient to disrupt dopaminergic function.
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The waters adjacent to the northeastern coast of Sakhalin Island, Russia, are an important feeding ground for the endangered western gray whale. Data on the energy available to foraging whales from their prey resources is required for researchers interested in modeling the bioenergetics of whale foraging, but little energy content information is available for the benthic prey communities of gray whales in this region. In this study, we describe the energy density (ED), biomass, and total energy availability (ED × biomass) of benthic prey sampled from two gray whale foraging areas adjacent to Sakhalin Island: the nearshore and offshore feeding areas. ED varied almost seven-fold among benthic taxa, ranging from 1.11 to 7.62 kJ/g wet mass. Although there was considerable variation within most prey groups, amphipods had the highest mean ED of all of groups examined (5.58 ± 1.44 kJ/g wet mass). Small sample sizes precluded us from detecting any seasonal or spatial differences in mean ED within or among taxa; however, mean biomass in the offshore feeding area was, in some cases, an order of magnitude higher than mean estimates in the nearshore feeding area, resulting in higher mean total energy available to foraging gray whales offshore (958-3313 kJ/m2) compared to nearshore (223-495 kJ/m2). While the proportion of total energy accounted for by amphipods was variable, this prey group generally made up a higher proportion of the total energy available in the benthos of the offshore feeding area than in the benthos of the nearshore feeding area. Data presented here will be used to inform bioenergetics modeling of the vital rates of mature females in an effort to improve understanding of population growth limits for western gray whales.
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Anfípodes , Baleias , Animais , Feminino , Monitoramento Ambiental , Biomassa , Coleta de DadosRESUMO
In 2015, two oil and gas companies conducted seismic surveys along the northeast coast of Sakhalin Island, Russia, near western gray whale (Eschrichtius robustus) feeding areas. This population of whales was listed as Critically Endangered at the time of the operations described here but has been reclassified as Endangered since 2018. The number and duration of the 2015 seismic surveys surpassed the level of previous seismic survey activity in this area, elevating concerns regarding disturbance of feeding gray whales and the potential for auditory injury. Exxon Neftegas Limited (ENL) developed a mitigation approach to address these concerns and, more importantly, implemented a comprehensive data collection strategy to assess the effectiveness of this approach. The mitigation approach prioritized completion of the seismic surveys closest to the nearshore feeding area as early in the season as possible, when fewer gray whales would be present. This was accomplished by increasing operational efficiency through the use of multiple seismic vessels and by establishing zones with specific seasonal criteria determining when air gun shutdowns would be implemented. These zones and seasonal criteria were based on pre-season modeled acoustic footprints of the air gun array and on gray whale distribution data collected over the previous 10 years. Real-time acoustic and whale sighting data were instrumental in the implementation of air gun shutdowns. The mitigation effectiveness of these shutdowns was assessed through analyzing short-term behavioral responses and shifts in gray whale distribution due to sound exposure. The overall mitigation strategy of an early survey completion was assessed through bioenergetics models that predict how reduced foraging activity might affect gray whale reproduction and maternal survival. This assessment relied on a total of 17 shore-based and 5 vessel-based teams collecting behavior, distribution, photo-identification, prey, and acoustic data. This paper describes the mitigation approach, the implementation of mitigation measures using real-time acoustic and gray whale location data, and the strategy to assess impacts and mitigation effectiveness.
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Monitoramento Ambiental , Baleias , Animais , Baleias/fisiologia , Acústica , Inquéritos e Questionários , Estações do AnoRESUMO
We used a stochastic dynamic programming (SDP) model to quantify the consequences of disturbance on pregnant western gray whales during one foraging season. The SDP model has a firm basis in bioenergetics, but detailed knowledge of minimum reproductive length of females (Lmin) and the relationship between length and reproductive success (Rfit) was lacking. We varied model assumptions to determine their effects on predictions of habitat use, proportion of animals disturbed, reproductive success, and the effects of disturbance. Smaller Lmin values led to higher predicted nearshore habitat use. Changes in Lmin and Rfit had little effect on predictions of the effect of disturbance. Reproductive success increased with increased Lmin and with higher probability of reproductive success by length. Multiple seismic surveys were conducted in 2015 off the northeast coast of Sakhalin Island, with concomitant benthic prey surveys, photo-identification studies, and whale distribution sampling, thus providing a unique opportunity to compare output from SDP models with empirical observations. SDP model predictions of reproductive success and habitat use were similar with and without acoustic disturbance, and SDP predictions of reproductive success and large-scale habitat use were generally similar to values and trends in the data. However, empirical estimates of the proportion of pregnant females nearshore were much higher than SDP model predictions (a large effect, measured by Cohen's d) during the first week, and the SDP model overestimated whale density in the south and underestimated density around the mouth of Piltun Bay. Such differences in nearshore habitat use would not affect SDP predictions of reproductive success or survival under the current seismic air gun disturbance scenario.
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Comportamento Alimentar , Baleias , Gravidez , Feminino , Animais , Monitoramento Ambiental , Ecossistema , AcústicaRESUMO
In the face of cumulative effects of oil and gas activities on the endangered western gray whale, informed management decisions rely on knowledge of gray whale spatial use patterns as a function of demographic group and prey energy. In particular, the gray whale foraging ground off Sakhalin Island consists of two distinct areas (nearshore and offshore) with the offshore feeding area exhibiting markedly high prey energy content. Based on photo-identification data collected from 2002 to 2015, we determined that gray whale use of the offshore feeding area increased with age. Pregnant females were more likely to be sighted only nearshore when nearshore prey energy and the proportion of nearshore energy from amphipods were higher. Likewise, females arriving with calves were less likely to be sighted offshore when the proportion of nearshore energy from amphipods was higher. Photo-identification effort in 2015 was increased substantially, with the intent of maximizing resighting data of individual whales to determine the relative proportion of different demographic groups utilizing the nearshore and offshore feeding areas. Comparing sighting data collected in 2015 with data from all previous years combined, mothers arriving with calves were sighted in the offshore feeding area earlier in 2015, with no evidence that they returned to forage nearshore later in the season. Other reproductive females constituted a higher proportion of the animals foraging nearshore prior to 2015, while juveniles were a higher proportion during 2015. Thus, the offshore feeding area is an important component of the gray whales' annual life cycle, particularly if nearshore prey energy continues to decline, and offshore anthropogenic activities need to be monitored and addressed.
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Anfípodes , Baleias , Gravidez , Feminino , Animais , Estações do Ano , Comportamento Alimentar , Monitoramento AmbientalRESUMO
Although pollination is one of the most crucial biological processes that ensures plant reproduction, its mechanisms are poorly understood. Especially in insect-mediated pollination, a pollen undergoes several attachment and detachment cycles when being transferred from anther to insect and from insect to stigma. The influence of the properties of pollen, insect and floral surfaces on the adhesion forces that mediate pollen transfer have been poorly studied. Here, we investigate the adhesive properties of Hypochaeris radicata pollen and their dependence on pollen aging by quantifying the pull-off forces from glass slides using centrifugation and atomic force microscopy. We found that the properties of the pollenkitt-the viscous, lipid liquid on the surface of most pollen grains-influences the forces necessary to detach a pollen from hydrophilic surfaces. Our results show that aged H. radicata pollen form weaker adhesions to hydrophilic glass than fresh ones. On the other hand, when a pollen grain ages in contact with glass, the adhesion between the two surfaces increases over time. This study shows for the first time the pollen aging effect on the pollination mechanism.
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BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) is a well-established treatment for patients with Parkinson's disease. Previous acute challenge studies suggested that short pulse widths might increase the therapeutic window while maintaining motor symptom control with a decrease in energy consumption. However, only little is known about the effect of short pulse width stimulation beyond the setting of an acute challenge. OBJECTIVE: To compare 4 weeks of STN-DBS with conventional pulse width stimulation (60 µs) to 4 weeks of STN-DBS with short pulse width stimulation (30 µs) regarding motor symptom control. METHODS: This study was a monocentric, double-blinded, randomized crossover non-inferiority trial investigating whether short pulse width stimulation with 30 µs maintains equal motor control as conventional 60 µs stimulation over a period of 4 weeks (German Clinical Trials Register No. DRKS00017528). Primary outcome was the difference in motor symptom control as assessed by a motor diary. Secondary outcomes included energy consumption measures, non-motor effects, side-effects, and quality of life. RESULTS: Due to a high dropout rate, the calculated sample size of 27 patients was not met and 24 patients with Parkinson's disease and STN-DBS were included in the final analysis. However, there were no differences in any investigated outcome parameter between the two treatment conditions. CONCLUSION: This study demonstrates that short pulse width settings (30 µs) provide non-inferior motor symptom control as conventional (60 µs) stimulation without significant differences in energy consumption. Future studies are warranted to evaluate a potential benefit of short pulse width settings in patients with pronounced dyskinesia.
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Estimulação Encefálica Profunda , Doença de Parkinson , Núcleo Subtalâmico , Estudos Cross-Over , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/terapia , Qualidade de Vida , Núcleo Subtalâmico/fisiologia , Resultado do TratamentoRESUMO
Resonant inelastic X-ray scattering in the XUV-regime has been implemented at BESSY II, pushing for a few-meV bandwidth in inelastic X-ray scattering at transition metal M-edges, rare earth N-edges and the K-edges of light elements up to carbon with full polarization control. The new dedicated low-energy beamline UE112-PGM1 has been designed to provide 1â µm vertical and 20â µm horizontal beam dimensions that serve together with sub-micrometre solid-state sample positioning as the source point for a high-resolution plane grating spectrometer and a high-transmission Rowland spectrometer for rapid overview spectra. The design and commissioning results of the beamline and high-resolution spectrometer are presented. Helium autoionization spectra demonstrate a resolving power of the beamline better than 10 000 at 64â eV with a 300â linesâ mm-1 grating while the measured resolving power of the spectrometer in the relevant energy range is 3000 to 6000.
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Miro1 has emerged as an interesting target to study Parkinson's disease-relevant pathways since it is a target of PINK1 and Parkin. Miro1 is a mitochondrial GTPase with the primary function of facilitating mitochondrial movement, and its knockout in mice is postnatally lethal. Here, we investigated the effect of the artificial RHOT1/Miro1 S156A mutation since it is a putative PINK1 phosphorylation site shown to be involved in Miro1 degradation and mitochondrial arrest during mitophagy. We gene-edited a homozygous phospho-null Miro1 S156A mutation in induced pluripotent stem cells to study the mutation in human dopaminergic neurons. This mutation causes a significant depletion of Miro1 steady-state protein levels and impairs further Miro1 degradation upon CCCP-induced mitophagy. However, mitochondrial mass measured by Tom20 protein levels, as well as mitochondrial area, are not affected in Miro1 S156A neurons. The mitochondria are slightly lengthened, which is in line with their increased turnover. Under basal conditions, we found no discernable effect of the mutation on mitochondrial movement in neurites. Interestingly, the S156A mutation leads to a significant reduction of mitochondrial oxygen consumption, which is accompanied by a depletion of OXPHOS complexes III and V. These effects are not mirrored by Miro1 knockdown in neuroblastoma cells, but they are observed upon differentiation. Undifferentiated Miro1 S156A neural precursor cells do not have decreased Miro1 levels nor OXPHOS complexes, suggesting that the effect of the mutation is tied to development. In mature dopaminergic neurons, the inhibition of Miro1 Ser156 phosphorylation elicits a mild loss of mitochondrial quality involving reduced mitochondrial membrane potential, which is sufficient to induce compensatory events involving OXPHOS. We suggest that the mechanism governing Miro1 steady-state levels depends on differentiation state and metabolic demand, thus underscoring the importance of this pathway in the pathobiology of Parkinson's disease.
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Células-Tronco Neurais , Doença de Parkinson , Proteínas rho de Ligação ao GTP , Animais , Neurônios Dopaminérgicos/metabolismo , Camundongos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Células-Tronco Neurais/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Fosforilação , Proteínas Quinases/metabolismo , Respiração , Serina/metabolismo , Proteínas rho de Ligação ao GTP/genéticaRESUMO
The GTPase Miro1 is tail anchored into the mitochondrial outer membrane and tethers mitochondria to molecular motors which is crucial for mitochondrial transport. Miro1 contains two EF hand, ion binding domains important for calcium sequestration. Miro1 is associated with Parkinson's disease (PD) due to its suggested interaction with PINK1 and Parkin. Rare variants in RHOT1 (encoding Miro1) were found in PD patients but Miro1's function in the brain is understudied. We gene edited three point mutations in healthy iPSCS EF hand R272Q was identified in a PD patient, S156A abolishes the proposed PINK1 phosphorylation site, K572R abolishes the main lysine targeted by pSer65-parkin.
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Edição de Genes , Mutação Puntual , Sistemas CRISPR-Cas/genética , Humanos , Proteínas Mitocondriais/genética , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
Acoustic disturbance is a growing conservation concern for wildlife populations because it can elicit physiological and behavioral responses that can have cascading impacts on population dynamics. State-dependent behavioral and life history models implemented via Stochastic Dynamic Programming (SDP) provide a natural framework for quantifying biologically meaningful population changes resulting from disturbance by linking environment, physiology, and metrics of fitness. We developed an SDP model using the endangered western gray whale (Eschrichtius robustus) as a case study because they experience acoustic disturbance on their summer foraging grounds. We modeled the behavior and physiological dynamics of pregnant females as they arrived on the feeding grounds and predicted the probability of female and offspring survival, with and without acoustic disturbance and in the presence/absence of high prey availability. Upon arrival in mid-May, pregnant females initially exhibited relatively random behavior before they transitioned to intensive feeding that resulted in continual fat mass gain until departure. This shift in behavior co-occurred with a change in spatial distribution; early in the season, whales were more equally distributed among foraging areas with moderate to high energy availability, whereas by mid-July whales transitioned to predominate use of the location that had the highest energy availability. Exclusion from energy-rich offshore areas led to reproductive failure and in extreme cases, mortality of adult females that had lasting impacts on population dynamics. Simulated disturbances in nearshore foraging areas had little to no impact on female survival or reproductive success at the population level. At the individual level, the impact of disturbance was unequally distributed across females of different lengths, both with respect to the number of times an individual was disturbed and the impact of disturbance on vital rates. Our results highlight the susceptibility of large capital breeders to reductions in prey availability, and indicate that who, where, and when individuals are disturbed are likely to be important considerations when assessing the impacts of acoustic activities. This model provides a framework to inform planned acoustic disturbances and assess the effectiveness of mitigation strategies for large capital breeders.
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Comportamento Alimentar , Baleias , Acústica , Animais , Feminino , Gravidez , Reprodução , Estações do Ano , Baleias/fisiologiaRESUMO
PURPOSE: The tryptophan-containing dipeptides isoleucine-tryptophan (IW) and tryptophan-leucine (WL) are angiotensin-converting enzyme (ACE)-inhibitors in vitro. These peptides are released by enzymatic hydrolysis of bovine whey protein. To exhibit ACE inhibition in vivo, peptides need to be absorbed into the circulatory system. This study aimed to determine the in vivo ACE-inhibitory potency of a whey protein hydrolysate (MPH), containing IW and WL, and to quantify plasma concentrations of these peptides after oral administration of MPH in healthy volunteers. Additionally, changes in blood pressure were investigated. RESULTS: After intake of 5 and 50 g MPH, plasma ACE activity was reduced to 86.4 ± 5.9 and 75.1 ± 6.9% of baseline activity, respectively. Although a clear ACE inhibition was measured, no effect on blood pressure was seen. Basal plasma concentrations of the tryptophan-containing dipeptides were 2.8 ± 0.7 nM for IW and 10.1 ± 1.8 nM for WL. After intake of 5-50 g MPH, peptide concentrations were dose dependently elevated to values between 12.5 ± 8.4 and 99.1 ± 58.7 nM for IW and 15.0 ± 4.3-34.9 ± 19.4 nM for WL. Administration of intact whey protein showed a minor ACE inhibition, probably caused by release of inhibitory peptides during gastrointestinal digestion. The increase of WL in plasma after intake of intact protein was similar to that determined after intake of MPH. In contrast, resulting IW concentrations were much lower after intake of intact whey protein when compared to MPH administration. CONCLUSION: After intake of MPH, plasma ACE activity decreased in parallel to the increase of IW and WL plasma concentrations. However, the resulting peptide concentrations cannot fully explain the reduction of ACE activity in plasma with a direct enzyme inhibition. Therefore, this study points to a gap in the understanding of the inhibitory action of these peptides in vivo. Thus, to further develop innovative food additives with ACE activity diminishing capabilities, it appears mandatory to better characterize the mode of action of these peptides.
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Inibidores da Enzima Conversora de Angiotensina/farmacologia , Hidrolisados de Proteína/farmacologia , Triptofano/sangue , Triptofano/farmacologia , Proteínas do Soro do Leite/sangue , Proteínas do Soro do Leite/farmacologia , Adulto , Inibidores da Enzima Conversora de Angiotensina/sangue , Pressão Sanguínea/efeitos dos fármacos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Hidrolisados de Proteína/sangue , Valores de Referência , Método Simples-CegoRESUMO
Clear cell renal cell carcinoma (ccRCC) is the most-prominent tumor type of kidney cancers. Resistance of renal cell carcinoma (RCC) against tumor therapy is often owing to apoptosis resistance, e.g., by overexpression of anti-apoptotic proteins. However, little is known about the role of the apoptosis inhibitor c-FLIP and its potential impact on death receptor-induced apoptosis in ccRCC cells. In this study, we demonstrate that c-FLIP is crucial for resistance against CD95L-induced apoptosis in four ccRCC cell lines. Strikingly, downregulation of c-FLIP expression by short hairpin RNA (shRNA)interference led to spontaneous caspase activation and apoptotic cell death. Of note, knockdown of all c-FLIP splice variants was required to induce apoptosis. Stimulation of ccRCC cells with CD95L induced NF-κB and MAP kinase survival pathways as revealed by phosphorylation of RelA/p65 and Erk1/2. Interestingly, CD95L surface expression was high in all cell lines analyzed, and CD95 but not TNF-R1 clustered at cell contact sites. Downstream of CD95, inhibition of the NF-κB pathway led to spontaneous cell death. Surprisingly, knockdown experiments revealed that c-FLIP inhibits NF-κB activation in the context of CD95 signaling. Thus, c-FLIP inhibits apoptosis and dampens NF-κB downstream of CD95 but allows NF-κB activation to a level sufficient for ccRCC cell survival. In summary, we demonstrate a complex CD95-FLIP-NF-κB-signaling circuit, in which CD95-CD95L interactions mediate a paracrine survival signal in ccRCC cells with c-FLIP and NF-κB both being required for inhibiting cell death and ensuring survival. Our findings might lead to novel therapeutic approaches of RCC by circumventing apoptosis resistance.
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Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/fisiologia , Carcinoma de Células Renais/patologia , Receptor fas/metabolismo , Apoptose/fisiologia , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Técnicas de Silenciamento de Genes , Humanos , NF-kappa B/metabolismo , Transdução de SinaisRESUMO
Managing the nonlethal effects of disturbance on wildlife populations has been a long-term goal for decision makers, managers, and ecologists, and assessment of these effects is currently required by European Union and United States legislation. However, robust assessment of these effects is challenging. The management of human activities that have nonlethal effects on wildlife is a specific example of a fundamental ecological problem: how to understand the population-level consequences of changes in the behavior or physiology of individual animals that are caused by external stressors. In this study, we review recent applications of a conceptual framework for assessing and predicting these consequences for marine mammal populations. We explore the range of models that can be used to formalize the approach and we identify critical research gaps. We also provide a decision tree that can be used to select the most appropriate model structure given the available data. Synthesis and applications: The implementation of this framework has moved the focus of discussion of the management of nonlethal disturbances on marine mammal populations away from a rhetorical debate about defining negligible impact and toward a quantitative understanding of long-term population-level effects. Here we demonstrate the framework's general applicability to other marine and terrestrial systems and show how it can support integrated modeling of the proximate and ultimate mechanisms that regulate trait-mediated, indirect interactions in ecological communities, that is, the nonconsumptive effects of a predator or stressor on a species' behavior, physiology, or life history.
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Enterohemorrhagic E. coli (EHEC) are serious bacterial pathogens which are able to cause a hemorrhagic colitis or the life-threatening hemolytic-uremic syndrome (HUS) in humans. EHEC strains can carry different numbers of phage-borne nanS-p alleles that are responsible for acetic acid release from mucin from bovine submaxillary gland and 5-N-acetyl-9-O-acetyl neuraminic acid (Neu5,9Ac2), a carbohydrate present in mucin. Thus, Neu5,9Ac2 can be transformed to 5-N-acetyl neuraminic acid, an energy source used by E. coli strains. We hypothesize that these NanS-p proteins are involved in competitive growth of EHEC in the gastrointestinal tract of humans and animals. The aim of the current study was to demonstrate and characterize the nanS-p alleles of the 2011 E. coli O104:H4 outbreak strain LB226692 and analyze whether the presence of multiple nanS-p alleles in the LB226692 genome causes a competitive growth advantage over a commensal E. coli strain. We detected and characterized five heterogeneous phage-borne nanS-p alleles in the genome of E. coli O104:H4 outbreak strain LB226692 by in silico analysis of its genome. Furthermore, successive deletion of all nanS-p alleles, subsequent complementation with recombinant NanS-p13-His, and in vitro co-culturing experiments with the commensal E. coli strain AMC 198 were conducted. We could show that nanS-p genes of E. coli O104:H4 are responsible for growth inhibition of strain AMC 198, when Neu5,9Ac2 was used as sole carbon source in co-culture. The results of this study let us suggest that multiple nanS-p alleles may confer a growth advantage by outcompeting other E. coli strains in Neu5,9Ac2 rich environments, such as mucus in animal and human gut.
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Colífagos/enzimologia , Infecções por Escherichia coli/microbiologia , Escherichia coli O104/crescimento & desenvolvimento , Escherichia coli O104/patogenicidade , Esterases/genética , Ácido N-Acetilneuramínico/metabolismo , Prófagos/enzimologia , Proteínas Virais/genética , Alelos , Animais , Carbono/metabolismo , Bovinos , Colífagos/genética , Simulação por Computador , Escherichia coli O104/metabolismo , Escherichia coli O104/virologia , Esterases/metabolismo , Genoma Bacteriano , Humanos , Mucinas/metabolismo , Neuraminidase/genética , Neuraminidase/metabolismo , Prófagos/genética , Proteínas Recombinantes/genética , Análise de Sequência de DNA , Proteínas Virais/metabolismoRESUMO
Integrating behavior and physiology is critical to formulating new hypotheses on the evolution of animal life-history strategies. Migratory capital breeders acquire most of the energy they need to sustain migration, gestation, and lactation before parturition. Therefore, when predicting the impact of environmental variation on such species, a mechanistic understanding of the physiology of their migratory behavior is required. Using baleen whales as a model system, we developed a dynamic state variable model that captures the interplay among behavioral decisions, energy, reproductive needs, and the environment. We applied the framework to blue whales (Balaenoptera musculus) in the eastern North Pacific Ocean and explored the effects of environmental and anthropogenic perturbations on female reproductive success. We demonstrate the emergence of migration to track prey resources, enabling us to quantify the trade-offs among capital breeding, body condition, and metabolic expenses. We predict that periodic climatic oscillations affect reproductive success less than unprecedented environmental changes do. The effect of localized, acute anthropogenic impacts depended on whales' behavioral response to the disturbance; chronic, but weaker, disturbances had little effect on reproductive success. Because we link behavior and vital rates by modeling individuals' energetic budgets, we provide a general framework to investigate the ecology of migration and assess the population consequences of disturbance, while identifying critical knowledge gaps.
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Migração Animal/fisiologia , Balaenoptera/fisiologia , Comportamento Alimentar , Modelos Biológicos , Animais , Balaenoptera/psicologia , Euphausiacea , Feminino , GravidezRESUMO
Sleep disordered breathing a very common disorder with prevalence rates of up to 49% in large epidemiological studies on subjects older than 40 years. A recent study showed that applying CPAP treatment to patients with sleep disordered breathing recruited by their number of apnea and hypopnea events alone, does improve sleepiness but does not improve overall cardiovascular mortality. Based on older large studies however it is knownthat sleep disordered breathing is a cardiovascular risk and that treatment lowers mortality and morbidity. These results appear to be contradictory. However, they might be explained if patient population investigated are carefully reviewed further, and if sleep apnea severity metrics are reconsidered. According to this, it appears that studies speak of different populations. Whereas epidemiological studies use sampled subjects willing to participate, earlier studies used patients contacting a sleep center with complaints and symptoms. In this paper two studies are presented with an assessment of anatomical metrics for upper airway morphology in order to derive parameters for better prediction. Different phenotypes can explain why some people benefit from treatment and others do not benefit equally. Therefore more than just counting apnea and hypopnea events is needed in order to identify patients at risk and patients who have a lower risk when treated. This will require large data set evaluations with hard outcome data.
Assuntos
Síndromes da Apneia do Sono , Pressão Positiva Contínua nas Vias Aéreas , Humanos , Nariz , Fenótipo , PrevalênciaRESUMO
The mitochondrial proteins TRAP1 and HTRA2 have previously been shown to be phosphorylated in the presence of the Parkinson's disease kinase PINK1 but the downstream signalling is unknown. HTRA2 and PINK1 loss of function causes parkinsonism in humans and animals. Here, we identified TRAP1 as an interactor of HTRA2 using an unbiased mass spectrometry approach. In our human cell models, TRAP1 overexpression is protective, rescuing HTRA2 and PINK1-associated mitochondrial dysfunction and suggesting that TRAP1 acts downstream of HTRA2 and PINK1. HTRA2 regulates TRAP1 protein levels, but TRAP1 is not a direct target of HTRA2 protease activity. Following genetic screening of Parkinson's disease patients and healthy controls, we also report the first TRAP1 mutation leading to complete loss of functional protein in a patient with late onset Parkinson's disease. Analysis of fibroblasts derived from the patient reveal that oxygen consumption, ATP output and reactive oxygen species are increased compared to healthy individuals. This is coupled with an increased pool of free NADH, increased mitochondrial biogenesis, triggering of the mitochondrial unfolded protein response, loss of mitochondrial membrane potential and sensitivity to mitochondrial removal and apoptosis. These data highlight the role of TRAP1 in the regulation of energy metabolism and mitochondrial quality control. Interestingly, the diabetes drug metformin reverses mutation-associated alterations on energy metabolism, mitochondrial biogenesis and restores mitochondrial membrane potential. In summary, our data show that TRAP1 acts downstream of PINK1 and HTRA2 for mitochondrial fine tuning, whereas TRAP1 loss of function leads to reduced control of energy metabolism, ultimately impacting mitochondrial membrane potential. These findings offer new insight into mitochondrial pathologies in Parkinson's disease and provide new prospects for targeted therapies.