Global modeling of nature's contributions to people Chaplin-Kramer, Rebecca; Sharp, Richard P; Weil, Charlotte ...
Science (American Association for the Advancement of Science),
10/2019, Letnik:
366, Številka:
6462
Journal Article
Recenzirano
The magnitude and pace of global change demand rapid assessment of nature and its contributions to people. We present a fine-scale global modeling of current status and future scenarios for several ...contributions: water quality regulation, coastal risk reduction, and crop pollination. We find that where people's needs for nature are now greatest, nature's ability to meet those needs is declining. Up to 5 billion people face higher water pollution and insufficient pollination for nutrition under future scenarios of land use and climate change, particularly in Africa and South Asia. Hundreds of millions of people face heightened coastal risk across Africa, Eurasia, and the Americas. Continued loss of nature poses severe threats, yet these can be reduced 3- to 10-fold under a sustainable development scenario.
Gap Junction (GJ) channels, including the most common Connexin 43 (Cx43), have fundamental roles in excitable tissues by facilitating rapid transmission of action potentials between adjacent cells. ...For instance, synchronization during each heartbeat is regulated by these ion channels at the cardiomyocyte cell-cell border. Cx43 protein has a short half-life, and rapid synthesis and timely delivery of those proteins to particular subdomains are crucial for the cellular organization of gap junctions and maintenance of intracellular coupling. Impairment in gap junction trafficking contributes to dangerous complications in diseased hearts such as the arrhythmias of sudden cardiac death. Of recent interest are the protein-protein interactions with the Cx43 carboxy-terminus. These interactions have significant impact on the full length Cx43 lifecycle and also contribute to trafficking of Cx43 as well as possibly other functions. We are learning that many of the known non-canonical roles of Cx43 can be attributed to the recently identified six endogenous Cx43 truncated isoforms which are produced by internal translation. In general, alternative translation is a new leading edge for proteome expansion and therapeutic drug development. This review highlights recent mechanisms identified in the trafficking of gap junction channels, involvement of other proteins contributing to the delivery of channels to the cell-cell border, and understanding of possible roles of the newly discovered alternatively translated isoforms in Cx43 biology. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.
Display omitted
•Gap junction channels are essential aspects of cardiomyocyte coupling which provide synchronous cardiac contraction.•The trafficking of gap junction channels through Targeted Delivery is important for maintenance of cardiac synchrony.•Seven different protein-isoforms of Cx43 are produced from the same GJA1 mRNA molecule by means of alternative translation.•20kDa alternatively translated isoform of Cx43 is a protein-chaperone to autoregulate trafficking of the full length protein.
Sexual transmission of HIV-1 is an inefficient process, with only one or few variants of the donor quasispecies establishing the new infection. A critical, and as yet unresolved, question is whether ...the mucosal bottleneck selects for viruses with increased transmission fitness. Here, we characterized 300 limiting dilution-derived virus isolates from the plasma, and in some instances genital secretions, of eight HIV-1 donor and recipient pairs. Although there were no differences in the amount of virion-associated envelope glycoprotein, recipient isolates were on average threefold more infectious (P = 0.0001), replicated to 1.4-fold higher titers (P = 0.004), were released from infected cells 4.2-fold more efficiently (P < 0.00001), and were significantly more resistant to type I IFNs than the corresponding donor isolates. Remarkably, transmitted viruses exhibited 7.8-fold higher IFNα2 (P < 0.00001) and 39-fold higher IFNβ (P < 0.00001) half-maximal inhibitory concentrations (IC50) than did donor isolates, and their odds of replicating in CD4⁺ T cells at the highest IFNα2 and IFNβ doses were 35-fold (P < 0.00001) and 250-fold (P < 0.00001) greater, respectively. Interestingly, pretreatment of CD4⁺ T cells with IFNβ, but not IFNα2, selected donor plasma isolates that exhibited a transmitted virus-like phenotype, and such viruses were also detected in the donor genital tract. These data indicate that transmitted viruses are phenotypically distinct, and that increased IFN resistance represents their most distinguishing property. Thus, the mucosal bottleneck selects for viruses that are able to replicate and spread efficiently in the face of a potent innate immune response.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are ...no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.
Natural climate solutions are not enough Anderson, Christa M; DeFries, Ruth S; Litterman, Robert ...
Science (American Association for the Advancement of Science),
03/2019, Letnik:
363, Številka:
6430
Journal Article
Recenzirano
Decarbonizing the economy must remain a critical priority
Stabilizing Earth's climate and limiting temperature increase to well below 2°C per the Paris Agreement requires a dramatic uptick in the ...rate of progress on reducing greenhouse gas (GHG) emissions. Natural climate solutions (NCS) can be a substantial contributor, while also providing valuable cobenefits for people and ecosystems. Although analyses of NCS have some differences in the GHG fluxes they consider, all include emissions sources (such as deforestation, land-use change, and agricultural practices), emissions sinks (such as reforestation and restoring degraded lands), and non–carbon dioxide (CO
2
) agricultural emissions (such as methane from livestock). Some of us have contributed to among the most optimistic assessments of the potential of NCS (
1
), whereas others have been more pessimistic (
2
,
3
). But one thing on which we agree, and which technical literature generally acknowledges, is that the benefits of NCS do not decrease the imperative for mitigation from the energy and industrial sectors (
2
,
4
,
5
). Yet this point sometimes gets lost in public-facing conversations for example, are forests “our best weapon for fighting carbon emissions” or, more realistically, just one “piece of the puzzle”? (
6
). Strategies for incorporating NCS with energy and industrial mitigation in the climate portfolio should not be “either/or” but “yes, and.”
Climate change, wine, and conservation Hannah, Lee; Roehrdanz, Patrick R.; Ikegami, Makihiko ...
Proceedings of the National Academy of Sciences - PNAS,
04/2013, Letnik:
110, Številka:
17
Journal Article
Recenzirano
Odprti dostop
Climate change is expected to impact ecosystems directly, such as through shifting climatic controls on species ranges, and indirectly, for example through changes in human land use that may result ...in habitat loss. Shifting patterns of agricultural production in response to climate change have received little attention as a potential impact pathway for ecosystems. Wine grape production provides a good test case for measuring indirect impacts mediated by changes in agriculture, because viticulture is sensitive to climate and is concentrated in Mediterranean climate regions that are global biodiversity hotspots. Here we demonstrate that, on a global scale, the impacts of climate change on viticultural suitability are substantial, leading to possible conservation conflicts in land use and freshwater ecosystems. Area suitable for viticulture decreases 25% to 73% in major wine producing regions by 2050 in the higher RCP 8.5 concentration pathway and 19% to 62% in the lower RCP 4.5. Climate change may cause establishment of vineyards at higher elevations that will increase impacts on upland ecosystems and may lead to conversion of natural vegetation as production shifts to higher latitudes in areas such as western North America. Attempts to maintain wine grape productivity and quality in the face of warming may be associated with increased water use for irrigation and to cool grapes through misting or sprinkling, creating potential for freshwater conservation impacts. Agricultural adaptation and conservation efforts are needed that anticipate these multiple possible indirect effects.
Archaeological and paleoecological evidence shows that by 10,000 BCE, all human societies employed varying degrees of ecologically transformative land use practices, including burning, hunting, ...species propagation, domestication, cultivation, and others that have left long-term legacies across the terrestrial biosphere. Yet, a lingering paradigm among natural scientists, conservationists, and policymakers is that human transformation of terrestrial nature is mostly recent and inherently destructive. Here, we use the most up-to-date, spatially explicit global reconstruction of historical human populations and land use to show that this paradigm is likely wrong. Even 12,000 y ago, nearly three quarters of Earth's land was inhabited and therefore shaped by human societies, including more than 95% of temperate and 90% of tropical woodlands. Lands now characterized as "natural," "intact," and "wild" generally exhibit long histories of use, as do protected areas and Indigenous lands, and current global patterns of vertebrate species richness and key biodiversity areas are more strongly associated with past patterns of land use than with present ones in regional landscapes now characterized as natural. The current biodiversity crisis can seldom be explained by the loss of uninhabited wildlands, resulting instead from the appropriation, colonization, and intensifying use of the biodiverse cultural landscapes long shaped and sustained by prior societies. Recognizing this deep cultural connection with biodiversity will therefore be essential to resolve the crisis.
Summary
Patients eligible for emergency laparotomy who do not proceed to surgery are not as well characterised as patients who do proceed to surgery. We studied patients eligible for laparotomy, as ...defined by National Emergency Laparotomy Audit criteria, from August 2015 to October 2016. We analysed the association of individual variables with survival and two composite scores: P‐POSSUM and a general survival model. Out of 314 patients, 214 (68%) underwent laparotomy and 100 (32%) did not. Median (IQR range) follow‐up was 1.3 (0.1–1.8 0.0–2.5) years for the cohort, 1.5 (1.1–2.0 0.0–2.6) years after laparotomy and 0.0 (0.0–1.1 0.0–2.2) years without laparotomy. There were 126/314 (40%) deaths in the follow‐up period, 52/214 (24%) deaths after laparotomy and 74/100 (74%) deaths without surgery. Ninety out of 126 deaths (71%) were within one month of hospital admission. Patient variables were different for the two groups, which when combined in the general survival model generated background median (IQR range) life expectancies of 12 (6–21 0–49) and 4 (2–6 0–36) years, respectively, p < 0.0001. ‘Poor fitness’ precluded laparotomy in 74/100 (74%) patients. The decision to not operate involved a consultant less often than the decision to operate: 66/100 (66%) vs. 178/214 (83%), p = 0.001. Our study supports the contention that survival beyond 30 postoperative days could be predicted reasonably accurately. Survival in patients who did not have laparotomy was shorter than expected. Emergency laparotomy might have prolonged survival in some patients.
Mitochondria form dynamic tubular networks that continually change their shape and move throughout the cell. In eukaryotes, these organellar gymnastics are controlled by numerous pathways that ...preserve proper mitochondrial morphology and function. The best understood of these are the fusion and fission pathways, which rely on conserved GTPases and their binding partners to regulate organelle connectivity and copy number in healthy cells and during apoptosis. In budding yeast, mitochondrial shape is also maintained by proteins acting in the tubulation pathway. Novel proteins and pathways that control mitochondrial dynamics continue to be discovered, indicating that the mechanisms governing this organelle's behavior are more sophisticated than previously appreciated. Here we review recent advances in the field of mitochondrial dynamics and highlight the importance of these pathways to human health.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Gaps in our understanding of genetic susceptibility to malignant hyperthermia (MH) limit the application and interpretation of genetic diagnosis of the condition. Our aim was to define the prevalence ...and role of variants in the three genes implicated in MH susceptibility in the largest comprehensively phenotyped MH cohort worldwide.
We initially included one individual from each positive family tested in the UK MH Unit since 1971 to detect variants in RYR1, CACNA1S, or STAC3. Screening for genetic variants has been ongoing since 1991 and has involved a range of techniques, most recently next generation sequencing. We assessed the pathogenicity of variants using standard guidelines, including family segregation studies. The prevalence of recurrent variants of unknown significance was compared with the prevalence reported in a large database of sequence variants in low-risk populations.
We have confirmed MH susceptibility in 795 independent families, for 722 of which we have a DNA sample. Potentially pathogenic variants were found in 555 families, with 25 RYR1 and one CACNA1S variants previously unclassified recurrent variants significantly over-represented (P<1×10−7) in our cohort compared with the Exome Aggregation Consortium database. There was genotype–phenotype discordance in 86 of 328 families suitable for segregation analysis. We estimate non-RYR1/CACNA1S/STAC3 susceptibility occurs in 14–23% of MH families.
Our data provide current estimates of the role of variants in RYR1, CACNA1S, and STAC3 in susceptibility to MH in a predominantly white European population.
PDF
