The African naked mole-rat’s (Heterocephalus glaber) social and subterranean lifestyle generates a hypoxic niche. Under experimental conditions, naked mole-rats tolerate hours of extreme hypoxia and ...survive 18 minutes of total oxygen deprivation (anoxia) without apparent injury. During anoxia, the naked mole-rat switches to anaerobic metabolism fueled by fructose, which is actively accumulated and metabolized to lactate in the brain. Global expression of the GLUT5 fructose transporter and high levels of ketohexokinase were identified as molecular signatures of fructose metabolism. Fructose-driven glycolytic respiration in naked mole-rat tissues avoids feedback inhibition of glycolysis via phosphofructokinase, supporting viability. The metabolic rewiring of glycolysis can circumvent the normally lethal effects of oxygen deprivation, a mechanism that could be harnessed to minimize hypoxic damage in human disease.
Recent surveillance has revealed the emergence of the SARS-CoV-2 Omicron variant (BA.1/B.1.1.529) harboring up to 36 mutations in spike protein, the target of neutralizing antibodies. Given its ...potential to escape vaccine-induced humoral immunity, we measured the neutralization potency of sera from 88 mRNA-1273, 111 BNT162b, and 40 Ad26.COV2.S vaccine recipients against wild-type, Delta, and Omicron SARS-CoV-2 pseudoviruses. We included individuals that received their primary series recently (<3 months), distantly (6–12 months), or an additional “booster” dose, while accounting for prior SARS-CoV-2 infection. Remarkably, neutralization of Omicron was undetectable in most vaccinees. However, individuals boosted with mRNA vaccines exhibited potent neutralization of Omicron, only 4–6-fold lower than wild type, suggesting enhanced cross-reactivity of neutralizing antibody responses. In addition, we find that Omicron pseudovirus infects more efficiently than other variants tested. Overall, this study highlights the importance of additional mRNA doses to broaden neutralizing antibody responses against highly divergent SARS-CoV-2 variants.
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•The SARS-CoV-2 Omicron variant harbors 34 mutations in the spike, more than other variants•Two doses of mRNA-based vaccines elicit poor neutralization of Omicron•Three mRNA vaccine doses elicit potent variant cross-neutralization, including Omicron•The Omicron pseudovirus infects cells more efficiently than other SARS-CoV-2 variants
SARS-CoV-2 Omicron variant pseudovirus exhibits escape from vaccine-induced humoral immunity. However, a third dose of COVID-19 mRNA vaccine elicited humoral immunity capable of cross-neutralizing this strain. In addition, pseudovirus produced with the Omicron spike exhibited more efficient transduction of ACE2-expressing target cells than other variants.
Heat waves have profoundly impacted biota globally over the past decade, especially where their ecological impacts are rapid, diverse, and broad-scale. Although usually considered in isolation for ...either terrestrial or marine ecosystems, heat waves can straddle ecosystems of both types at subcontinental scales, potentially impacting larger areas and taxonomic breadth than previously envisioned. Using climatic and multi-species demographic data collected in Western Australia, we show that a massive heat wave event straddling terrestrial and maritime ecosystems triggered abrupt, synchronous, and multi-trophic ecological disruptions, including mortality, demographic shifts and altered species distributions. Tree die-off and coral bleaching occurred concurrently in response to the heat wave, and were accompanied by terrestrial plant mortality, seagrass and kelp loss, population crash of an endangered terrestrial bird species, plummeting breeding success in marine penguins, and outbreaks of terrestrial wood-boring insects. These multiple taxa and trophic-level impacts spanned >300,000 km
-comparable to the size of California-encompassing one terrestrial Global Biodiversity Hotspot and two marine World Heritage Areas. The subcontinental multi-taxa context documented here reveals that terrestrial and marine biotic responses to heat waves do not occur in isolation, implying that the extent of ecological vulnerability to projected increases in heat waves is underestimated.
Globally, Phytophthora cinnamomi is listed as one of the 100 worst invasive alien species and active management is required to reduce impact and prevent spread in both horticulture and natural ...ecosystems. Conversely, there are regions thought to be suitable for the pathogen where no disease is observed. We developed a climex model for the global distribution of P. cinnamomi based on the pathogen's response to temperature and moisture and by incorporating extensive empirical evidence on the presence and absence of the pathogen. The climex model captured areas of climatic suitability where P. cinnamomi occurs that is congruent with all available records. The model was validated by the collection of soil samples from asymptomatic vegetation in areas projected to be suitable by the model for which there were few records. DNA was extracted, and the presence or absence of P. cinnamomi was determined by high‐throughput sequencing (HTS). While not detected using traditional isolation methods, HTS detected P. cinnamomi at higher elevations in eastern Australia and central Tasmania as projected by the climex model. Further support for the climex model was obtained using the large data set from south‐west Australia where the proportion of positive records in an area is related to the Ecoclimatic Index value for the same area. We provide for the first time a comprehensive global map of the current P. cinnamomi distribution, an improved climex model of the distribution, and a projection to 2080 of the distribution with predicted climate change. This information provides the basis for more detailed regional‐scale modelling and supports risk assessment for governments to plan management of this important soil‐borne plant pathogen.
As stem cells undergo differentiation, mitochondrial DNA (mtDNA) copy number is strictly regulated in order that specialized cells can generate appropriate levels of adenosine triphosphate (ATP) ...through oxidative phosphorylation (OXPHOS) to undertake their specific functions. It is not understood whether tumor-initiating cells regulate their mtDNA in a similar manner or whether mtDNA is essential for tumorigenesis. We show that human neural stem cells (hNSCs) increased their mtDNA content during differentiation in a process that was mediated by a synergistic relationship between the nuclear and mitochondrial genomes and results in increased respiratory capacity. Differentiating multipotent glioblastoma cells failed to match the expansion in mtDNA copy number, patterns of gene expression and increased respiratory capacity observed in hNSCs. Partial depletion of glioblastoma cell mtDNA rescued mtDNA replication events and enhanced cell differentiation. However, prolonged depletion resulted in impaired mtDNA replication, reduced proliferation and induced the expression of early developmental and pro-survival markers including POU class 5 homeobox 1 (OCT4) and sonic hedgehog (SHH). The transfer of glioblastoma cells depleted to varying degrees of their mtDNA content into immunocompromised mice resulted in tumors requiring significantly longer to form compared with non-depleted cells. The number of tumors formed and the time to tumor formation was relative to the degree of mtDNA depletion. The tumors derived from mtDNA depleted glioblastoma cells recovered their mtDNA copy number as part of the tumor formation process. These outcomes demonstrate the importance of mtDNA to the initiation and maintenance of tumorigenesis in glioblastoma multiforme.
Pluripotent blastomeres of mammalian pre-implantation embryos and embryonic stem cells (ESCs) are characterized by limited oxidative capacity and great reliance on anaerobic respiration. Early ...pre-implantation embryos and undifferentiated ESCs possess small and immature mitochondria located around the nucleus, have low oxygen consumption and express high levels of glycolytic enzymes. However, as embryonic cells and ESCs lose pluripotency and commit to a specific cell fate, the expression of mtDNA transcription and replication factors is upregulated and the number of mitochondria and mtDNA copies/cell increases. Moreover, upon cellular differentiation, mitochondria acquire an elongated morphology with swollen cristae and dense matrices, migrate into wider cytoplasmic areas and increase the levels of oxygen consumption and ATP production as a result of the activation of the more efficient, aerobic metabolism. Since pluripotency seems to be associated with anaerobic metabolism and a poorly developed mitochondrial network and differentiation leads to activation of mitochondrial biogenesis according to the metabolic requirements of the specific cell type, it is hypothesized that reprogramming of somatic cells towards a pluripotent state, by somatic cell nuclear transfer (SCNT), transcription-induced pluripotency or creation of pluripotent cell hybrids, requires acquisition of mitochondrial properties characteristic of pluripotent blastomeres and ESCs.
Published prevalence estimates of nonsuicidal self‐injury (NSSI) among nonclinical samples are highly heterogeneous, raising concerns about their reliability and hindering attempts to explore the ...alleged increase in NSSI over time. Accordingly, the objectives of this study were to investigate the influence of methodological factors on heterogeneity in NSSI prevalence estimates, explore changes over time, and estimate overall international NSSI prevalence. Results showed that methodological factors contributed over half (51.6%) of the heterogeneity in prevalence estimates, and, after adjusting for these factors, NSSI prevalence did not increase over time. Overall, pooled NSSI prevalence was 17.2% among adolescents, 13.4% among young adults, and 5.5% among adults. Clearly, development of standardized methodology in NSSI research is crucial if accurate estimates are desired.
C-Reactive Protein Is an Independent Predictor of Risk for the Development of Diabetes in the West of Scotland Coronary Prevention
Study
Dilys J. Freeman 1 ,
John Norrie 2 ,
Muriel J. Caslake 3 ,
...Allan Gaw 3 ,
Ian Ford 2 ,
Gordon D.O. Lowe 4 ,
Denis St. J. O’Reilly 3 ,
Chris J. Packard 3 ,
Naveed Sattar 3 and
for the West of Scotland Coronary Prevention Study Group
1 Department of Obstetrics and Gynaecology, University of Glasgow, Glasgow, U.K.
2 Robertson Centre for Biostatistics, University of Glasgow, Glasgow, U.K.
3 Department of Pathological Biochemistry, University of Glasgow, Glasgow, U.K.
4 Department of Medicine, University of Glasgow, Glasgow, U.K.
Abstract
Accumulating evidence implicates inflammation as a potential pathway in the pathogenesis of type 2 diabetes. The objective
of the present study was to assess the ability of C-reactive protein (CRP) to predict the development of diabetes in middle-aged
men in the West of Scotland Coronary Prevention Study. Baseline plasma samples for CRP measurement were available for 5,245
men of whom 127 were classified as having a transition from normal glucose control to overt diabetes during the study, based
on American Diabetes Association criteria. Baseline CRP was an important predictor of the development of diabetes in univariate
analysis (hazard ratio HR for an increase of 1 SD = 1.55; 95% CI 1.32–1.82; P < 0.0001). In multivariate analysis, CRP remained a predictor of diabetes development (HR 1.30; 95% CI 1.07–1.58; P = 0.0075) independent of other clinically employed predictors, including baseline BMI and fasting triglyceride and glucose
concentrations. Moreover, there was a graded increase in risk across CRP quintiles throughout the study, evident at even 1
year of follow-up. The highest quintile (CRP >4.18 mg/l) was associated with a greater than threefold risk of developing diabetes
(HR 3.07; 95% CI 1.33–7.10) in a multivariate analysis at 5 years. Thus, CRP predicts the development of type 2 diabetes in
middle-aged men independently of established risk factors. Because CRP, the most commonly used acute-phase protein in clinical
practice, is very stable in serum, our observations have clinical potential in helping to better predict individuals destined
to develop type 2 diabetes. They also add to the notion that low-grade inflammation is important in the pathogenesis of type
2 diabetes.
Footnotes
Address correspondence and reprint requests to Dr. Dilys Freeman, Department of Obstetrics and Gynaecology, Royal Infirmary,
Queen Elizabeth Building, 10 Alexandra Parade, Glasgow, G31 2ER, U.K. E-mail: d.freeman{at}clinmed.gla.ac.uk .
A.G. has received honoraria for lectures from Bristol-Myers Squibb, AstraZeneca, MSD, Pfizer, and Sankyo. I.F. has received
honoraria for speaking engagements from Bristol-Myers Squibb.
Received for publication 12 November 2001 and accepted in revised form 15 February 2002.
ADA, American Diabetes Association; CRP, C-reactive protein; HR, hazard ratio; WCC, white cell count; WOSCOPS, West of Scotland
Coronary Prevention Study.
DIABETES
Background: Studies indicate that low plasma 25-hydroxyvitamin D 25(OH)D is associated with a range of disease processes, many of which are inflammatory. However, other lipid-soluble vitamins ...decrease during the systemic inflammatory response, and this response may confound the interpretation of plasma 25(OH)D.
Objective: The objective was to examine whether plasma 25(OH)D concentrations change during evolution of the systemic inflammatory response.
Design: Patients (n = 33) who underwent primary knee arthroplasty had venous blood samples collected preoperatively and postoperatively (beginning 6–12 h after surgery and on each morning for 5 d) for the measurement of 25(OH) D, vitamin D–binding protein, parathyroid hormone (PTH), calcium, C-reactive protein, and albumin. A final sample was collected at 3 mo.
Results: Preoperatively, most patients were 25(OH)D deficient (<50 nmol/L) and had secondary hyperparathyroidism (PTH > 5 pmol/L). Age, sex, body mass index, season, medical history, and medication use were not associated with significant differences in preoperative plasma 25(OH)D concentrations. By day 2 there was a large increase in C-reactive protein concentrations (P < 0.001) and a significant decrease in 25(OH)D of ≈40% (P < 0.001). C-reactive protein, 25(OH)D, and calculated free 25(OH)D had not returned to preoperative concentrations by 5 d postoperatively (all P < 0.001). At 3 mo, 25(OH)D and free 25(OH)D remained significantly lower (20% and 30%, respectively; P < 0.01).
Conclusion: Plasma concentrations of 25(OH)D decrease after an inflammatory insult and therefore are unlikely to be a reliable measure of 25(OH)D status in subjects with evidence of a significant systemic inflammatory response.
We show theoretically that the photoionization process in a hollow-core photonic crystal fiber filled with a Raman-inactive noble gas leads to a constant acceleration of solitons in the time domain ...with a continuous shift to higher frequencies, limited only by ionization loss. This phenomenon is opposite to the well-known Raman self-frequency redshift of solitons in solid-core glass fibers. We also predict the existence of unconventional long-range nonlocal soliton interactions leading to spectral and temporal soliton clustering. Furthermore, if the core is filled with a Raman-active molecular gas, spectral transformations between redshifted, blueshifted, and stabilized solitons can take place in the same fiber.
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