Malaria is an infectious disease caused by parasites of the genus Plasmodium, which leads to approximately one million deaths per annum worldwide. Chemical validation of new antimalarial targets is ...urgently required in view of rising resistance to current drugs. One such putative target is the enzyme N-myristoyltransferase, which catalyses the attachment of the fatty acid myristate to protein substrates (N-myristoylation). Here, we report an integrated chemical biology approach to explore protein myristoylation in the major human parasite P. falciparum, combining chemical proteomic tools for identification of the myristoylated and glycosylphosphatidylinositol-anchored proteome with selective small-molecule N-myristoyltransferase inhibitors. We demonstrate that N-myristoyltransferase is an essential and chemically tractable target in malaria parasites both in vitro and in vivo, and show that selective inhibition of N-myristoylation leads to catastrophic and irreversible failure to assemble the inner membrane complex, a critical subcellular organelle in the parasite life cycle. Our studies provide the basis for the development of new antimalarials targeting N-myristoyltransferase.
Marine bivalves are well known for their impressive lifespans. Like trees, bivalves grow by accretion and record age and size throughout ontogeny in their shell. Bivalves, however, can form growth ...increments at several different periodicities depending on their local environment. Thus, establishing lifespans and growth rates of marine bivalves requires a proper identification of annual growth increments. Here, we use isotope sclerochronology to decipher the accretionary growth record of modern
Astarte borealis
from the White Sea, Russia (N 67°05.70′; E 32°40.85′). Unlike winter growth increments observed in many other cold-temperate and boreal bivalve and limpet species, prominent growth increments in
A. borealis
corresponded to the most negative values in the oxygen isotope (δ
18
O) time series indicating that they formed during summer. Furthermore, summer growth increments do not coincide with the external concentric ridges on the shell making the latter feature an unreliable indicator of age. Similar to many other polar bivalves,
A. borealis
shows slow growth and long life. The von Bertalanffy growth equation for our sample is
H
t
= 29.39*(1 −
e
(− 0.11(
t
−(− 1.86))
). Lifespans of individuals examined here (
n
= 18) range from 16 to 48 years. Given its impressive longevity and widespread polar distribution,
A. borealis
may be a potentially valuable skeletal archive for monitoring environmental conditions in the Arctic Ocean and boreal seas in the face of changing climate.
Objective To evaluate the association between newborn acylcarnitine profiles and the subsequent development of necrotizing enterocolitis (NEC) with the use of routinely collected newborn screening ...data in infants born preterm. Study design A retrospective cohort study was conducted with the use of discharge records for infants born preterm admitted to neonatal intensive care units in California from 2005 to 2009 who had linked state newborn screening results. A model-development cohort of 94 110 preterm births from 2005 to 2008 was used to develop a risk-stratification model that was then applied to a validation cohort of 22 992 births from 2009. Results Fourteen acylcarnitine levels and acylcarnitine ratios were associated with increased risk of developing NEC. Each log unit increase in C5 and free carnitine /(C16 + 18:1) was associated with a 78% and a 76% increased risk for developing NEC, respectively (OR 1.78, 95% CI 1.53-2.02, and OR 1.76, 95% CI 1.51-2.06). Six acylcarnitine levels, along with birth weight and total parenteral nutrition, identified 89.8% of newborns with NEC in the model-development cohort (area under the curve 0.898, 95% CI 0.889-0.907) and 90.8% of the newborns with NEC in the validation cohort (area under the curve 0.908, 95% CI 0.901-0.930). Conclusions Abnormal fatty acid metabolism was associated with prematurity and the development of NEC. Metabolic profiling through newborn screening may serve as an objective biologic surrogate of risk for the development of disease and thus facilitate disease-prevention strategies.
Mean body size in marine animals has increased more than 100-fold since the Cambrian, a discovery that brings to attention the key life-history parameters of lifespan and growth rate that ultimately ...determine size. Variation in these parameters is not well understood on the planet today, much less in deep time. Here, we present a new global database of maximum reported lifespan and shell growth coupled with body size data for 1 148 populations of marine bivalves and show that (i) lifespan increases, and growth rate decreases, with latitude, both across the group as a whole and within well-sampled species, (ii) growth rate, and hence metabolic rate, correlates inversely with lifespan, and (iii) opposing trends in lifespan and growth combined with high variance obviate any demonstrable pattern in body size with latitude. Our observations suggest that the proposed increase in metabolic activity and demonstrated increase in body size of organisms over the Phanerozoic should be accompanied by a concomitant shift towards faster growth and/or shorter lifespan in marine bivalves. This prediction, testable from the fossil record, may help to explain one of the more fundamental patterns in the evolutionary and ecological history of animal life on this planet.
The field of sclerochronology has long been known to paleobiologists. Yet, despite the central role of growth rate, age, and body size in questions related to macroevolution and evolutionary ecology, ...these types of studies and the data they produce have received only episodic attention from paleobiologists since the field's inception in the 1960s. It is time to reconsider their potential. Not only can sclerochronological data help to address long-standing questions in paleobiology, but they can also bring to light new questions that would otherwise have been impossible to address. For example, growth rate and life-span data, the very data afforded by chronological growth increments, are essential to answer questions related not only to heterochrony and hence evolutionary mechanisms, but also to body size and organism energetics across the Phanerozoic. While numerous fossil organisms have accretionary skeletons, bivalves offer perhaps one of the most tangible and intriguing pathways forward, because they exhibit clear, typically annual, growth increments and they include some of the longest-lived, non-colonial animals on the planet. In addition to their longevity, modern bivalves also show a latitudinal gradient of increasing life span and decreasing growth rate with latitude that might be related to the latitudinal diversity gradient. Is this a recently developed phenomenon or has it characterized much of the group's history? When and how did extreme longevity evolve in the Bivalvia? What insights can the growth increments of fossil bivalves provide about hypotheses for energetics through time? In spite of the relative ease with which the tools of sclerochronology can be applied to these questions, paleobiologists have been slow to adopt sclerochronological approaches. Here, we lay out an argument and the methods for a path forward in paleobiology that uses sclerochronology to answer some of our most pressing questions.
One of the longest-lived, noncolonial animals on the planet today is a bivalve that attains life spans in excess of 500 years and lives in a cold, seasonally food-limited setting. Separating the ...influence of temperature and food availability on life span in modern settings is difficult, as these two conditions covary. The life spans of fossil animals can provide insights into the role of environment in the evolution of extreme longevity that are not available from studies of modern taxa. We examine bivalves from the unique, nonanalogue, warm and high-latitude setting of Seymour Island, Antarctica, during the greenhouse intervals of the Late Cretaceous and Paleogene. Despite significant sampling limitations, we find that all 11 species examined are both slow growing and long-lived, especially when compared with modern bivalves living in similar temperature settings. While cool temperatures have long been thought to be a key factor in promoting longevity, our findings suggest an important role for caloric restriction brought about by the low and seasonal light regime of the high latitudes. Our life-history data, spanning three different families, emphasize that longevity is in part governed by environmental rather than solely phylogenetic or ecologic factors. Such findings have implications for both modern and ancient latitudinal diversity gradients, as a common correlate of slow growth and long life is delayed reproduction, which limits the potential for evolutionary change. While life spans of modern bivalves are well studied, data on life spans of fossil bivalves are sparse and largely anecdotal. Life histories of organisms from deep time can not only elucidate the controls on life span but also add a new dimension to our understanding of macroevolutionary patterns.
Traditional isotope sclerochronology employing isotope ratio mass spectrometry has been used for decades to determine the periodicity of growth increment formation in marine organisms with ...accretionary growth. Despite its well-demonstrated capabilities, it is not without limitation. The most significant of these being the volume of carbonate powder required for analysis with conventional drill-sampling techniques, which limit sampling to early in ontogeny when growth is fast or to species that reach relatively large sizes. In species like
Astarte borealis
(Schumacher, 1817), a common component of Arctic boreal seas, traditional methods of increment analysis are difficult, because the species is typically long-lived, slow growing, and forms extremely narrowly spaced growth increments. Here, we use Secondary Ion Mass Spectrometry (SIMS) to analyze δ
18
O in 10-μm-diameter spots and resolve the seasonal timing of growth increment formation in
Astarte borealis
in the southeastern Baltic Sea. In the individaul sampled here, dark growth increments can form in either the fall, winter, or spring. Furthermore, growth increment data from two populations (RFP3S = 54.7967° N, 12.38787° E; WA = 54.86775° N, 14.09832° E) indicate that in the Baltic Sea,
A. borealis
is moderately long-lived (at least 43 years) and slow growing (von Bertalanffy
k
values 0.08 and 0.06). Our results demonstrate the potential of
A. borealis
to be a recorder of Baltic Sea seasonality over the past century using both live- and dead-collected shells, and also the ability of SIMS analysis to broaden the spectrum of bivalves used in sclerocrhonological work.
Introduction
Astarte borealis
holds great potential as an archive of seasonal paleoclimate, especially due to its long lifespan (several decades to more than a century) and ubiquitous distribution ...across high northern latitudes. Furthermore, recent work demonstrates that the isotope geochemistry of the aragonite shell is a faithful proxy of environmental conditions. However, the exceedingly slow growth rates of
A. borealis
in some locations (<0.2mm/year) make it difficult to achieve seasonal resolution using standard micromilling techniques for conventional stable isotope analysis. Moreover, oxygen isotope (δ
18
O) records from species inhabiting brackish environments are notoriously difficult to use as paleoclimate archives because of the simultaneous variation in temperature and δ
18
O
water
values.
Methods
Here we use secondary ion mass spectrometry (SIMS) to microsample an
A. borealis
specimen from the southern Baltic Sea, yielding 451 SIMS δ
18
O
shell
values at sub-monthly resolution.
Results
SIMS δ
18
O
shell
values exhibit a quasi-sinusoidal pattern with 24 local maxima and minima coinciding with 24 annual growth increments between March 1977 and the month before specimen collection in May 2001.
Discussion
Age-modeled SIMS δ
18
O
shell
values correlate significantly with both
in situ
temperature measured from shipborne CTD casts (r
2
= 0.52, p<0.001) and sea surface temperature from the ORAS5-SST global reanalysis product for the Baltic Sea region (r
2
= 0.42, p<0.001). We observe the strongest correlation between SIMS δ
18
O
shell
values and salinity when both datasets are run through a 36-month LOWESS function (r
2
= 0.71, p < 0.001). Similarly, we find that LOWESS-smoothed SIMS δ
18
O
shell
values exhibit a moderate correlation with the LOWESS-smoothed North Atlantic Oscillation (NAO) Index (r
2
= 0.46, p<0.001). Change point analysis supports that SIMS δ
18
O
shell
values capture a well-documented regime shift in the NAO circa 1989. We hypothesize that the correlation between the SIMS δ
18
O
shell
time series and the NAO is enhanced by the latter’s influence on the regional covariance of water temperature and δ
18
O
water
values on interannual and longer timescales in the Baltic Sea. These results showcase the potential for SIMS δ
18
O
shell
values in
A. borealis
shells to provide robust paleoclimate information regarding hydroclimate variability from seasonal to decadal timescales.
Mwanganda's Village (MGD) and Bruce (BRU) are two open-air site complexes in northern Malawi with deposits dating to between 15 and 58 thousand years ago (ka) and containing Middle Stone Age (MSA) ...lithic assemblages. The sites have been known since 1966 and 1965, respectively, but lacked chronometric and site formation data necessary for their interpretation. The area hosts a rich stone artifact record, eroding from and found within alluvial fan deposits exhibiting poor preservation of organic materials. Although this generally limits opportunities for site-based environmental reconstructions, MGD and BRU are located at the distal margins of the alluvial fan, where lacustrine lagoonal deposits were overprinted by a calcrete paleosol. This has created locally improved organic preservation and allowed us to obtain ecological data from pollen, phytoliths, and pedogenic carbonates, producing a regional- to site-scale environmental context for periods of site use and abandonment. Here, we integrate the ecological data into a detailed site formation history, based on field observations and micromorphology, supplemented by cathodoluminescence microscopy and μ-XRF. By comparing local, on-site environmental proxies with more regional indicators, we can better evaluate how MSA hunter-gatherers made decisions about the use of resources across the landscape. Our data indicate that while tree cover similar to modern miombo woodland and evergreen gallery forest prevailed at most times, MSA hunter-gatherers chose more locally open environments for activities that resulted in a lithic artifact record at multiple locations between 51 and 15 ka.
•MSA foragers in a forested landscape in Malawi chose locally more open environments.•Micromorphology tackles complex formation histories at open-air sites.•Calcrete paleosols at the margins of Lake Malawi preserve environmental proxies.•Combining multi-scale proxies increases understanding of human activity in the landscape.
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