We surveyed morphotectonic markers along the central part of the Gurvan Bulag thrust, a fault that ruptured with the Bogd fault during the Gobi-Altay earthquake (1957, M 8.3), to document climatic ...and tectonic processes along the fault for the late Pleistocene-Holocene period. The markers were dated using 10 Be produced in situ. Two major periods of alluviation ended at 131 ± 20 and 16 ± 4.8 ka. These appear to be contemporaneous with global climatic changes at the terminations of marine isotope stages (MIS) 6 and 2. The vertical slip rates, determined from offset measurements and surfaces ages, are 0.14 ± 0.03 mm/yr over the late Pleistocene-Holocene and between 0.44 ± 0.11 and 1.05 ± 0.25 mm/yr since the end of the late Pleistocene. The higher of these slip rates for the last $16 kyr is consistent with paleoseismic investigations along the fault Prentice et al., 2002, and suggests that, at the end of late Pleistocene, the fault evolved from quiescence to having recurrence intervals of 4.0 ± 1.2 kyr for surface ruptures with $4 m vertical offset (similar to that of 1957). The inferred recurrence interval is comparable to that of the Bogd fault (3.7 ± 1.3 kyr) suggesting that the two faults may have ruptured together also earlier during the last $16 kyr.
We surveyed morphotectonic markers along the central part of the Gurvan Bulag thrust, a fault that ruptured with the Bogd fault during the Gobi‐Altay earthquake (1957,
M
8.3), to document climatic ...and tectonic processes along the fault for the late Pleistocene‐Holocene period. The markers were dated using
10
Be produced in situ. Two major periods of alluviation ended at 131 ± 20 and 16 ± 4.8 ka. These appear to be contemporaneous with global climatic changes at the terminations of marine isotope stages (MIS) 6 and 2. The vertical slip rates, determined from offset measurements and surfaces ages, are 0.14 ± 0.03 mm/yr over the late Pleistocene‐Holocene and between 0.44 ± 0.11 and 1.05 ± 0.25 mm/yr since the end of the late Pleistocene. The higher of these slip rates for the last ∼16 kyr is consistent with paleoseismic investigations along the fault
Prentice et al.
, 2002
, and suggests that, at the end of late Pleistocene, the fault evolved from quiescence to having recurrence intervals of 4.0 ± 1.2 kyr for surface ruptures with ∼4 m vertical offset (similar to that of 1957). The inferred recurrence interval is comparable to that of the Bogd fault (3.7 ± 1.3 kyr) suggesting that the two faults may have ruptured together also earlier during the last ∼16 kyr.
From early 2003 to mid-2013, the total mass of ice in Greenland declined at a progressively increasing rate. In mid-2013, an abrupt reversal occurred, and very little net ice loss occurred in the ...next 12–18 months. Gravity Recovery and Climate Experiment (GRACE) and global positioning system (GPS) observations reveal that the spatial patterns of the sustained acceleration and the abrupt deceleration in mass loss are similar. The strongest accelerations tracked the phase of the North Atlantic Oscillation (NAO). The negative phase of the NAO enhances summertime warming and insolation while reducing snowfall, especially in west Greenland, driving surface mass balance (SMB) more negative, as illustrated using the regional climate model MAR. The spatial pattern of accelerating mass changes reflects the geography of NAO-driven shifts in atmospheric forcing and the ice sheet’s sensitivity to that forcing. We infer that southwest Greenland will become a major future contributor to sea level rise.
Understanding potential trajectories in health and drivers of health is crucial to guiding long-term investments and policy implementation. Past work on forecasting has provided an incomplete ...landscape of future health scenarios, highlighting a need for a more robust modelling platform from which policy options and potential health trajectories can be assessed. This study provides a novel approach to modelling life expectancy, all-cause mortality and cause of death forecasts —and alternative future scenarios—for 250 causes of death from 2016 to 2040 in 195 countries and territories.
We modelled 250 causes and cause groups organised by the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) hierarchical cause structure, using GBD 2016 estimates from 1990–2016, to generate predictions for 2017–40. Our modelling framework used data from the GBD 2016 study to systematically account for the relationships between risk factors and health outcomes for 79 independent drivers of health. We developed a three-component model of cause-specific mortality: a component due to changes in risk factors and select interventions; the underlying mortality rate for each cause that is a function of income per capita, educational attainment, and total fertility rate under 25 years and time; and an autoregressive integrated moving average model for unexplained changes correlated with time. We assessed the performance by fitting models with data from 1990–2006 and using these to forecast for 2007–16. Our final model used for generating forecasts and alternative scenarios was fitted to data from 1990–2016. We used this model for 195 countries and territories to generate a reference scenario or forecast through 2040 for each measure by location. Additionally, we generated better health and worse health scenarios based on the 85th and 15th percentiles, respectively, of annualised rates of change across location-years for all the GBD risk factors, income per person, educational attainment, select intervention coverage, and total fertility rate under 25 years in the past. We used the model to generate all-cause age-sex specific mortality, life expectancy, and years of life lost (YLLs) for 250 causes. Scenarios for fertility were also generated and used in a cohort component model to generate population scenarios. For each reference forecast, better health, and worse health scenarios, we generated estimates of mortality and YLLs attributable to each risk factor in the future.
Globally, most independent drivers of health were forecast to improve by 2040, but 36 were forecast to worsen. As shown by the better health scenarios, greater progress might be possible, yet for some drivers such as high body-mass index (BMI), their toll will rise in the absence of intervention. We forecasted global life expectancy to increase by 4·4 years (95% UI 2·2 to 6·4) for men and 4·4 years (2·1 to 6·4) for women by 2040, but based on better and worse health scenarios, trajectories could range from a gain of 7·8 years (5·9 to 9·8) to a non-significant loss of 0·4 years (–2·8 to 2·2) for men, and an increase of 7·2 years (5·3 to 9·1) to essentially no change (0·1 years –2·7 to 2·5) for women. In 2040, Japan, Singapore, Spain, and Switzerland had a forecasted life expectancy exceeding 85 years for both sexes, and 59 countries including China were projected to surpass a life expectancy of 80 years by 2040. At the same time, Central African Republic, Lesotho, Somalia, and Zimbabwe had projected life expectancies below 65 years in 2040, indicating global disparities in survival are likely to persist if current trends hold. Forecasted YLLs showed a rising toll from several non-communicable diseases (NCDs), partly driven by population growth and ageing. Differences between the reference forecast and alternative scenarios were most striking for HIV/AIDS, for which a potential increase of 120·2% (95% UI 67·2–190·3) in YLLs (nearly 118 million) was projected globally from 2016–40 under the worse health scenario. Compared with 2016, NCDs were forecast to account for a greater proportion of YLLs in all GBD regions by 2040 (67·3% of YLLs 95% UI 61·9–72·3 globally); nonetheless, in many lower-income countries, communicable, maternal, neonatal, and nutritional (CMNN) diseases still accounted for a large share of YLLs in 2040 (eg, 53·5% of YLLs 95% UI 48·3–58·5 in Sub-Saharan Africa). There were large gaps for many health risks between the reference forecast and better health scenario for attributable YLLs. In most countries, metabolic risks amenable to health care (eg, high blood pressure and high plasma fasting glucose) and risks best targeted by population-level or intersectoral interventions (eg, tobacco, high BMI, and ambient particulate matter pollution) had some of the largest differences between reference and better health scenarios. The main exception was sub-Saharan Africa, where many risks associated with poverty and lower levels of development (eg, unsafe water and sanitation, household air pollution, and child malnutrition) were projected to still account for substantive disparities between reference and better health scenarios in 2040.
With the present study, we provide a robust, flexible forecasting platform from which reference forecasts and alternative health scenarios can be explored in relation to a wide range of independent drivers of health. Our reference forecast points to overall improvements through 2040 in most countries, yet the range found across better and worse health scenarios renders a precarious vision of the future—a world with accelerating progress from technical innovation but with the potential for worsening health outcomes in the absence of deliberate policy action. For some causes of YLLs, large differences between the reference forecast and alternative scenarios reflect the opportunity to accelerate gains if countries move their trajectories toward better health scenarios—or alarming challenges if countries fall behind their reference forecasts. Generally, decision makers should plan for the likely continued shift toward NCDs and target resources toward the modifiable risks that drive substantial premature mortality. If such modifiable risks are prioritised today, there is opportunity to reduce avoidable mortality in the future. However, CMNN causes and related risks will remain the predominant health priority among lower-income countries. Based on our 2040 worse health scenario, there is a real risk of HIV mortality rebounding if countries lose momentum against the HIV epidemic, jeopardising decades of progress against the disease. Continued technical innovation and increased health spending, including development assistance for health targeted to the world's poorest people, are likely to remain vital components to charting a future where all populations can live full, healthy lives.
Bill & Melinda Gates Foundation.
Site-directed mutagenesis of the cloned subfragment-1 (S-1) region of the unc-54 gene, encoding the myosin heavy chain B (MHC B) from Caenorhabditis elegans, has been used to locate binding sites for ...the regulatory and essential light chains. MHC B S-1 synthesized in Escherichia coli co-migrated with rabbit skeletal muscle myosin S-1 (Mr 90,000), was recognized by anti-nematode myosin antiserum on immunoblots, and specifically bound to 125I-labelled regulatory and essential light chains in a gel overlay assay. Deletion of 102 residues from the C terminus (mutant 655) reduced regulatory and essential light-chain binding to about 30% and 20% of wild-type levels, respectively. Similar reductions in relative binding of the two light chains were seen with mutant 534, in which 38 residues were deleted from the C terminus. Potential binding sites within 75 residues of the C terminus of S-1 were mapped by construction of five other mutant S-1 clones (398, 399, 400, 409 and 411) containing internal deletions of ten to 12 amino acid residues. These showed up to 30% reductions in their ability to bind essential light chains, but did not differ significantly from wild-type in their ability to bind regulatory light chains. Another mutant, 415, containing a deletion of a conserved acidic hexapeptide, E-D-I-R-D-E, showed enhancement of binding of regulatory and essential light chains to 150% and 165% of wild-type levels. Hence, the major binding sites for both light chains are within 38 amino acid residues of the C terminus.
The importance of mitochondrial biosynthesis in stimulus secretion coupling in the insulin-producing beta-cell probably equals that of ATP production. In glucose-induced insulin secretion, the rate ...of pyruvate carboxylation is very high and correlates more strongly with the glucose concentration the beta-cell is exposed to (and thus with insulin release) than does pyruvate decarboxylation, which produces acetyl-CoA for metabolism in the citric acid cycle to produce ATP. The carboxylation pathway can increase the levels of citric acid cycle intermediates, and this indicates that anaplerosis, the net synthesis of cycle intermediates, is important for insulin secretion. Increased cycle intermediates will alter mitochondrial processes, and, therefore, the synthesized intermediates must be exported from mitochondria to the cytosol (cataplerosis). This further suggests that these intermediates have roles in signaling insulin secretion. Although evidence is quite good that all physiological fuel secretagogues stimulate insulin secretion via anaplerosis, evidence is just emerging about the possible extramitochondrial roles of exported citric acid cycle intermediates. This article speculates on their potential roles as signaling molecules themselves and as exporters of equivalents of NADPH, acetyl-CoA and malonyl-CoA, as well as alpha-ketoglutarate as a substrate for hydroxylases. We also discuss the "succinate mechanism," which hypothesizes that insulin secretagogues produce both NADPH and mevalonate. Finally, we discuss the role of mitochondria in causing oscillations in beta-cell citrate levels. These parallel oscillations in ATP and NAD(P)H. Oscillations in beta-cell plasma membrane electrical potential, ATP/ADP and NAD(P)/NAD(P)H ratios, and glycolytic flux are known to correlate with pulsatile insulin release. Citrate oscillations might synchronize oscillations of individual mitochondria with one another and mitochondrial oscillations with oscillations in glycolysis and, therefore, with flux of pyruvate into mitochondria. Thus citrate oscillations may synchronize mitochondrial ATP production and anaplerosis with other cellular oscillations.
There are three isocitrate dehydrogenases (IDHs) in the pancreatic insulin cell; IDH1 (cytosolic) and IDH2 (mitochondrial) use NADP(H). IDH3 is mitochondrial, uses NAD(H) and was believed to be the ...IDH that supports the citric acid cycle.
With shRNAs targeting mRNAs for these enzymes we generated cell lines from INS-1 832/13 cells with severe (80%–90%) knockdown of the mitochondrial IDHs separately and together in the same cell line.
With knockdown of both mitochondrial IDH's mRNA, enzyme activity and protein level, (but not with knockdown of only one mitochondrial IDH) glucose- and BCH (an allosteric activator of glutamate dehydrogenase)-plus-glutamine-stimulated insulin release were inhibited. Cellular levels of citrate, α-ketoglutarate, malate and ATP were altered in patterns consistent with blockage at the mitochondrial IDH reactions. We were able to generate only 50% knockdown of Idh1 mRNA in multiple cell lines (without inhibition of insulin release) possibly because greater knockdown of IDH1 was not compatible with cell line survival.
The mitochondrial IDHs are redundant for insulin secretion. When both enzymes are severely knocked down, their low activities (possibly assisted by transport of IDH products and other metabolic intermediates from the cytosol into mitochondria) are sufficient for cell growth, but inadequate for insulin secretion when the requirement for intermediates is certainly more rapid. The results also indicate that IDH2 can support the citric acid cycle.
As almost all mammalian cells possess substantial amounts of all three IDH enzymes, the biological principles suggested by these results are probably extrapolatable to many tissues.
•Mitochondrial isocitrate dehydrogenases were knocked down with shRNA in beta cells.•Lowering one mitochondrial isocitrate dehydrogenase did not inhibit insulin release.•Lowering both mitochondrial IDHs in a single cell line inhibited insulin release.•Mitochondrial NADP-isocitrate dehydrogenase can support the citric acid cycle.•Mitochondrial isocitrate dehydrogenases play redundant roles in insulin secretion.
The Greenland GPS Network (GNET) uses the Global Positioning System (GPS) to measure the displacement of bedrock exposed near the margins of the Greenland ice sheet. The entire network is uplifting ...in response to past and present-day changes in ice mass. Crustal displacement is largely accounted for by an annual oscillation superimposed on a sustained trend. The oscillation is driven by earth's elastic response to seasonal variations in ice mass and air mass (i.e., atmospheric pressure). Observed vertical velocities are higher and often much higher than predicted rates of postglacial rebound (PGR), implying that uplift is usually dominated by the solid earth's instantaneous elastic response to contemporary losses in ice mass rather than PGR. Superimposed on longer-term trends, an anomalous 'pulse' of uplift accumulated at many GNET stations during an approximate six-month period in 2010. This anomalous uplift is spatially correlated with the 2010 melting day anomaly.
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