Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the ...oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD+ and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.
Display omitted
•A specific decline in mitochondrially encoded genes occurs during aging in muscle•Nuclear NAD+ levels regulate mitochondrial homeostasis independently of PGC-1α/β•Declining NAD+ during aging causes pseudohypoxia, which disrupts OXPHOS function•Raising nuclear NAD+ in old mice reverses pseudohypoxia and metabolic dysfunction
Aging disrupts an NAD+-dependent nuclear-mitochondrial communication pathway, causing a decline in the mitochondrially encoded oxidative phosphorylation components relative to nuclear-encoded components. Raising NAD+ levels in old mice alleviates the pseudohypoxic conditions that disrupt the communication pathway, reversing this mitochondrial defect.
Restoring gene flow into small, isolated populations can alleviate genetic load and decrease extinction risk (i.e., genetic rescue), yet gene flow is rarely augmented as a conservation strategy. Due ...to this discrepancy between opportunity and action, a recent call was made for widespread genetic rescue attempts. However, several aspects of augmenting gene flow are poorly understood, including the magnitude and duration of beneficial effects and when deleterious effects are likely to occur. We discuss the remaining uncertainties of genetic rescue in order to promote and direct future research and to hasten progress toward implementing this potentially powerful conservation strategy on a broader scale.
Genetic rescue has helped prevent the extinction of several populations, yet augmented gene flow is rarely used as a conservation strategy.Recent calls have been made for a paradigm shift in the conservation of small, isolated populations away from managing populations in isolation and toward widespread restoration of gene flow.Several aspects of genetic rescue remain poorly understood.Genetic rescue is inherently an eco-evolutionary process, and successful genetic rescue attempts have been part of comprehensive conservation plans that consider habitat, life history, and genetics.Genomics is being increasingly used in the implementation and monitoring of genetic rescue attempts.
Milk, in addition to nourishing the neonate, provides a range of complex glycans whose construction ensures a specific enrichment of key members of the gut microbiota in the nursing infant, a ...consortium known as the milk-oriented microbiome. Milk glycoproteins are thought to function similarly, as specific growth substrates for bifidobacteria common to the breast-fed infant gut. Recently, a cell wall-associated endo-β-N-acetylglucosaminidase (EndoBI-1) found in various infant-borne bifidobacteria was shown to remove a range of intact N-linked glycans. We hypothesized that these released oligosaccharide structures can serve as a sole source for the selective growth of bifidobacteria. We demonstrated that EndoBI-1 released N-glycans from concentrated bovine colostrum at the pilot scale. EndoBI-1-released N-glycans supported the rapid growth of Bifidobacterium longum subsp. infantis (B. infantis), a species that grows well on human milk oligosaccharides, but did not support growth of Bifidobacterium animalis subsp. lactis (B. lactis), a species which does not. Conversely, B. infantis ATCC 15697 did not grow on the deglycosylated milk protein fraction, clearly demonstrating that the glycan portion of milk glycoproteins provided the key substrate for growth. Mass spectrometry-based profiling revealed that B. infantis consumed 73% of neutral and 92% of sialylated N-glycans, while B. lactis degraded only 11% of neutral and virtually no (<1%) sialylated N-glycans. These results provide mechanistic support that N-linked glycoproteins from milk serve as selective substrates for the enrichment of infant-associated bifidobacteria capable of carrying out the initial deglycosylation. Moreover, released N-glycans were better growth substrates than the intact milk glycoproteins, suggesting that EndoBI-1 cleavage is a key initial step in consumption of glycoproteins. Finally, the variety of N-glycans released from bovine milk glycoproteins suggests that they may serve as novel prebiotic substrates with selective properties similar to those of human milk oligosaccharides.
It has been previously shown that glycoproteins serve as growth substrates for bifidobacteria. However, which part of a glycoprotein (glycans or polypeptides) is responsible for this function was not known. In this study, we used a novel enzyme to cleave conjugated N-glycans from milk glycoproteins and tested their consumption by various bifidobacteria. The results showed that the glycans selectively stimulated the growth of B. infantis, which is a key infant gut microbe. The selectivity of consumption of individual N-glycans was determined using advanced mass spectrometry (nano-liquid chromatography chip-quadrupole time of flight mass spectrometry nano-LC-Chip-Q-TOF MS) to reveal that B. infantis can consume the range of glycan structures released from whey protein concentrate.
Diabetic nephropathy is a serious complication of diabetes mellitus and is associated with considerable morbidity and high mortality. There is increasing evidence to suggest that dysregulation of the ...epigenome is involved in diabetic nephropathy. We assessed whether epigenetic modification of DNA methylation is associated with diabetic nephropathy in a case-control study of 192 Irish patients with type 1 diabetes mellitus (T1D). Cases had T1D and nephropathy whereas controls had T1D but no evidence of renal disease.
We performed DNA methylation profiling in bisulphite converted DNA from cases and controls using the recently developed Illumina Infinium HumanMethylation27 BeadChip, that enables the direct investigation of 27,578 individual cytosines at CpG loci throughout the genome, which are focused on the promoter regions of 14,495 genes.
Singular Value Decomposition (SVD) analysis indicated that significant components of DNA methylation variation correlated with patient age, time to onset of diabetic nephropathy, and sex. Adjusting for confounding factors using multivariate Cox-regression analyses, and with a false discovery rate (FDR) of 0.05, we observed 19 CpG sites that demonstrated correlations with time to development of diabetic nephropathy. Of note, this included one CpG site located 18 bp upstream of the transcription start site of UNC13B, a gene in which the first intronic SNP rs13293564 has recently been reported to be associated with diabetic nephropathy.
This high throughput platform was able to successfully interrogate the methylation state of individual cytosines and identified 19 prospective CpG sites associated with risk of diabetic nephropathy. These differences in DNA methylation are worthy of further follow-up in replication studies using larger cohorts of diabetic patients with and without nephropathy.
Protists, which are single-celled eukaryotes, critically influence the ecology and chemistry of marine ecosystems, but genome-based studies of these organisms have lagged behind those of other ...microorganisms. However, recent transcriptomic studies of cultured species, complemented by meta-omics analyses of natural communities, have increased the amount of genetic information available for poorly represented branches on the tree of eukaryotic life. This information is providing insights into the adaptations and interactions between protists and other microorganisms and macroorganisms, but many of the genes sequenced show no similarity to sequences currently available in public databases. A better understanding of these newly discovered genes will lead to a deeper appreciation of the functional diversity and metabolic processes in the ocean. In this Review, we summarize recent developments in our understanding of the ecology, physiology and evolution of protists, derived from transcriptomic studies of cultured strains and natural communities, and discuss how these novel large-scale genetic datasets will be used in the future.
It is currently unclear whether the GluN2 subtype influences NMDA receptor (NMDAR) excitotoxicity. We report that the toxicity of NMDAR-mediated Ca2+ influx is differentially controlled by the ...cytoplasmic C-terminal domains of GluN2B (CTD2B) and GluN2A (CTD2A). Studying the effects of acute expression of GluN2A/2B-based chimeric subunits with reciprocal exchanges of their CTDs revealed that CTD2B enhances NMDAR toxicity, compared to CTD2A. Furthermore, the vulnerability of forebrain neurons in vitro and in vivo to NMDAR-dependent Ca2+ influx is lowered by replacing the CTD of GluN2B with that of GluN2A by targeted exon exchange in a mouse knockin model. Mechanistically, CTD2B exhibits stronger physical/functional coupling to the PSD-95-nNOS pathway, which suppresses protective CREB activation. Dependence of NMDAR excitotoxicity on the GluN2 CTD subtype can be overcome by inducing high levels of NMDAR activity. Thus, the identity (2A versus 2B) of the GluN2 CTD controls the toxicity dose-response to episodes of NMDAR activity.
► The CTD of GluN2B promotes excitotoxicity better than that of GluN2A ► GluN2 CTD subtype differences are seen in both WT and chimeric 2A/2B subunits ► The GluN2B CTD couples to a prodeath PSD-95/nNOS-dependent CREB shut-off pathway
Martel et al. find that the two subtypes (2A versus 2B) of the GluN2 C-terminal domain differentially couple to the CREB shut-off pathway, causing distinct effects on NMDA receptor-mediated neuronal death both in vitro and in vivo.
Thermodynamics of prediction Still, Susanne; Sivak, David A; Bell, Anthony J ...
Physical review letters,
09/2012, Volume:
109, Issue:
12
Journal Article
Peer reviewed
Open access
A system responding to a stochastic driving signal can be interpreted as computing, by means of its dynamics, an implicit model of the environmental variables. The system's state retains information ...about past environmental fluctuations, and a fraction of this information is predictive of future ones. The remaining nonpredictive information reflects model complexity that does not improve predictive power, and thus represents the ineffectiveness of the model. We expose the fundamental equivalence between this model inefficiency and thermodynamic inefficiency, measured by dissipation. Our results hold arbitrarily far from thermodynamic equilibrium and are applicable to a wide range of systems, including biomolecular machines. They highlight a profound connection between the effective use of information and efficient thermodynamic operation: any system constructed to keep memory about its environment and to operate with maximal energetic efficiency has to be predictive.
Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and ...uncertainty about its effectiveness remains.
We conducted a pragmatic randomized trial with an integrated cost-effectiveness analysis in 56 hospitals in England. Patients were randomly assigned to receive either EGDT (a 6-hour resuscitation protocol) or usual care. The primary clinical outcome was all-cause mortality at 90 days.
We enrolled 1260 patients, with 630 assigned to EGDT and 630 to usual care. By 90 days, 184 of 623 patients (29.5%) in the EGDT group and 181 of 620 patients (29.2%) in the usual-care group had died (relative risk in the EGDT group, 1.01; 95% confidence interval CI, 0.85 to 1.20; P=0.90), for an absolute risk reduction in the EGDT group of -0.3 percentage points (95% CI, -5.4 to 4.7). Increased treatment intensity in the EGDT group was indicated by increased use of intravenous fluids, vasoactive drugs, and red-cell transfusions and reflected by significantly worse organ-failure scores, more days receiving advanced cardiovascular support, and longer stays in the intensive care unit. There were no significant differences in any other secondary outcomes, including health-related quality of life, or in rates of serious adverse events. On average, EGDT increased costs, and the probability that it was cost-effective was below 20%.
In patients with septic shock who were identified early and received intravenous antibiotics and adequate fluid resuscitation, hemodynamic management according to a strict EGDT protocol did not lead to an improvement in outcome. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment Programme; ProMISe Current Controlled Trials number, ISRCTN36307479.).
Global, repeat satellite imagery serves as an essential tool to understand ecological patterns and processes over diverse temporal and spatial scales. Recently, the use of spaceborne imagery has ...become indispensable for monitoring giant kelp, a globally distributed foundation species that displays variable seasonal and interannual dynamics. In order to develop and maintain a continuous and spatially expansive time series, we describe a fully automated protocol to classify giant kelp canopy biomass across three Landsat sensors. This required correcting kelp canopy estimates to account for changes in the spectral response functions between the three sensors by simulating data using hyperspectral imagery. Combining multiple sensors also necessitated the use of an extended (15 year) time series of diver estimated kelp biomass to validate each sensor. We also describe a novel gap filling technique using known spatial scales of kelp biomass synchrony to correct for missing data due to the Enhanced Thematic Mapper Plus scan line corrector failure. These developments have led to a publicly available 34-year, seasonal time series of kelp canopy biomass across ~1500 km of California coastline.
We then use this time series to examine the role of temporal and spatial scale on the detection of long-term biomass trends. We found that kelp canopy biomass trends are associated with trends in low frequency marine climate oscillations, like the North Pacific Gyre Oscillation. Long-term (~20 year) increases in the state of the North Pacific Gyre Oscillation have led to a cooler, nutrient-rich environment that benefits the growth of giant kelp across a large portion of the kelp biomass time series, however recent warming events have led to weak, or nonexistent trends over the length of the time series. The cyclical nature of these low frequency marine climate oscillations complicates the detection of trends that may be associated with anthropogenic climate change. A longer and continuous time series is needed to analyze long-term canopy biomass trends outside of natural low frequency climate variability for giant kelp ecosystems along the coast of California, if we are to make accurate assessments of the impacts of climate change.
•Developed a consistent kelp canopy biomass time series merging three Landsat sensors•Investigated and corrected for the role of tidal height in Landsat estimates•Developed a gap filling algorithm based on spatial synchrony patterns•Marine climate oscillations are associated with long-term kelp biomass trends.•Argues for longer, continuous satellite records for the detection of climate change
Abstract This article, inspired by Colin Jones’ ‘Bourgeois revolution revivified’, calls on historians to pay renewed attention to the social and economic contexts of the French Enlightenment, and ...its relationship to the rise of commercial capitalism. It criticizes influential works in the ‘social history of ideas’ for placing too much emphasis on the compatibility of the Enlightenment and Old Regime social structures, and instead suggests that French Enlightenment writing had a symbiotic relationship to the period’s consumer revolution. This relationship becomes clear if we recognize that consumerism centrally involved practices of self-cultivation. French Enlightenment writing not only provided the expanding reading public of the eighteenth century with tools and guides for self-cultivation, but actively encouraged the process through the styles and genres with which it sought to appeal to and interact with this public. The article concludes by noting that in the political context of late eighteenth-century France, social experience and intellectual exploration alike metamorphosed into pointed social critique, which worked especially to the benefit of the upper Third Estate—that is to say, France’s emerging bourgeoisie.
PDF
