An underlying hallmark of cancers is their genomic instability, which is associated with a greater propensity to accumulate DNA damage. Historical treatment of cancer by radiotherapy and DNA-damaging ...chemotherapy is based on this principle, yet it is accompanied by significant collateral damage to normal tissue and unwanted side effects. Targeted therapy based on inhibiting the DNA damage response (DDR) in cancers offers the potential for a greater therapeutic window by tailoring treatment to patients with tumors lacking specific DDR functions. The recent approval of olaparib (Lynparza), the poly (ADP-ribose) polymerase (PARP) inhibitor for treating tumors harboring BRCA1 or BRCA2 mutations, represents the first medicine based on this principle, exploiting an underlying cause of tumor formation that also represents an Achilles’ heel. This review highlights the different concepts behind targeting DDR in cancer and how this can provide significant opportunities for DDR-based therapies in the future.
An underlying hallmark of cancers is their genomic instability, which is associated with a greater propensity to accumulate DNA damage. Historical treatment of cancer by radiotherapy and DNA-damaging chemotherapy is based on this principle, yet it is accompanied by significant collateral damage to normal tissue and unwanted side effects. Targeted therapy based on inhibiting the DNA damage response (DDR) in cancers offers the potential for a greater therapeutic window by tailoring treatment to patients with tumors lacking specific DDR functions. The recent approval of olaparib (Lynparza), the poly (ADP-ribose) polymerase (PARP) inhibitor for treating tumors harboring BRCA1 or BRCA2 mutations, represents the first medicine based on this principle, exploiting an underlying cause of tumor formation that also represents an Achilles’ heel. This review highlights the different concepts behind targeting DDR in cancer and how this can provide significant opportunities for DDR-based therapies in the future.
Poly(ADP-ribose) polymerase (PARP) inhibitors are the first DNA damage response targeted agents approved for cancer therapy. Here, we focus on their molecular mechanism of action by PARP "trapping" ...and what this means for both clinical monotherapy and combination with chemotherapeutic agents.
Mendelian randomization, a method to infer causal relationships, is confounded by genetic correlations reflecting shared etiology. We developed a model in which a latent causal variable mediates the ...genetic correlation; trait 1 is partially genetically causal for trait 2 if it is strongly genetically correlated with the latent causal variable, quantified using the genetic causality proportion. We fit this model using mixed fourth moments Formula: see text and Formula: see text of marginal effect sizes for each trait; if trait 1 is causal for trait 2, then SNPs affecting trait 1 (large Formula: see text) will have correlated effects on trait 2 (large α
α
), but not vice versa. In simulations, our method avoided false positives due to genetic correlations, unlike Mendelian randomization. Across 52 traits (average n = 331,000), we identified 30 causal relationships with high genetic causality proportion estimates. Novel findings included a causal effect of low-density lipoprotein on bone mineral density, consistent with clinical trials of statins in osteoporosis.
Background
There is currently very limited information on the nature and prevalence of post‐COVID‐19 symptoms after hospital discharge.
Methods
A purposive sample of 100 survivors discharged from a ...large University hospital were assessed 4 to 8 weeks after discharge by a multidisciplinary team of rehabilitation professionals using a specialist telephone screening tool designed to capture symptoms and impact on daily life. EQ‐5D‐5L telephone version was also completed.
Results
Participants were between 29 and 71 days (mean 48 days) postdischarge from hospital. Thirty‐two participants required treatment in intensive care unit (ICU group) and 68 were managed in hospital wards without needing ICU care (ward group). New illness‐related fatigue was the most common reported symptom by 72% participants in ICU group and 60.3% in ward group. The next most common symptoms were breathlessness (65.6% in ICU group and 42.6% in ward group) and psychological distress (46.9% in ICU group and 23.5% in ward group). There was a clinically significant drop in EQ5D in 68.8% in ICU group and in 45.6% in ward group.
Conclusions
This is the first study from the United Kingdom reporting on postdischarge symptoms. We recommend planning rehabilitation services to manage these symptoms appropriately and maximize the functional return of COVID‐19 survivors.
Highlights
This is the first UK study reporting on longer term symptoms in individuals recovering from COVID‐19.
New illness‐related fatigue, breathlessness and psychological distress were commonly reported at 7 weeks after discharge from hospital with a clinically significant drop in the quality of life of many individuals.
Symptoms were present in both ward and ICU managed individuals, the prevalence being higher in those who required ICU care.
Rehabilitation care for COVID‐19 survivors must therefore be need‐focused, delivered by specialist multidisciplinary team and planned for the longer term to meet the needs of these individuals.
1000 dams down and counting O'Connor, J. E.; Duda, J. J.; Grant, G. E.
Science (American Association for the Advancement of Science),
05/2015, Letnik:
348, Številka:
6234
Journal Article
Recenzirano
Dam removals are reconnecting rivers in the United States
Forty years ago, the demolition of large dams was mostly fiction, notably plotted in Edward Abbey's novel
The Monkey Wrench Gang.
Its 1975 ...publication roughly coincided with the end of large-dam construction in the United States. Since then, dams have been taken down in increasing numbers as they have filled with sediment, become unsafe or inefficient, or otherwise outlived their usefulness (
1
) (see the figure, panel A). Last year's removals of the 64-m-high Glines Canyon Dam and the 32-m-high Elwha Dam in northwestern Washington State were among the largest yet, releasing over 10 million cubic meters of stored sediment. Published studies conducted in conjunction with about 100 U.S. dam removals and at least 26 removals outside the United States are now providing detailed insights into how rivers respond (
2
,
3
).
Dam removal: Listening in Foley, M. M.; Bellmore, J. R.; O'Connor, J. E. ...
Water resources research,
July 2017, 2017-07-00, 20170701, Letnik:
53, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Dam removal is widely used as an approach for river restoration in the United States. The increase in dam removals—particularly large dams—and associated dam‐removal studies over the last few decades ...motivated a working group at the USGS John Wesley Powell Center for Analysis and Synthesis to review and synthesize available studies of dam removals and their findings. Based on dam removals thus far, some general conclusions have emerged: (1) physical responses are typically fast, with the rate of sediment erosion largely dependent on sediment characteristics and dam‐removal strategy; (2) ecological responses to dam removal differ among the affected upstream, downstream, and reservoir reaches; (3) dam removal tends to quickly reestablish connectivity, restoring the movement of material and organisms between upstream and downstream river reaches; (4) geographic context, river history, and land use significantly influence river restoration trajectories and recovery potential because they control broader physical and ecological processes and conditions; and (5) quantitative modeling capability is improving, particularly for physical and broad‐scale ecological effects, and gives managers information needed to understand and predict long‐term effects of dam removal on riverine ecosystems. Although these studies collectively enhance our understanding of how riverine ecosystems respond to dam removal, knowledge gaps remain because most studies have been short (< 5 years) and do not adequately represent the diversity of dam types, watershed conditions, and dam‐removal methods in the U.S.
Key Points
Dam removal is an increasingly common approach to river restoration in the United States
Dam‐removal studies provide insights on key controls influencing the physical and ecological responses to dam removal
Although many aspects of physical and ecological systems react quickly to dam removal, overall response trajectories depend on how and where dams are removed and overall watershed conditions
Emotional Intelligence (EI) emerged in the 1990s as an ability based construct analogous to general Intelligence. However, over the past 3 decades two further, conceptually distinct forms of EI have ...emerged (often termed "trait EI" and "mixed model EI") along with a large number of psychometric tools designed to measure these forms. Currently more than 30 different widely-used measures of EI have been developed. Although there is some clarity within the EI field regarding the types of EI and their respective measures, those external to the field are faced with a seemingly complex EI literature, overlapping terminology, and multiple published measures. In this paper we seek to provide guidance to researchers and practitioners seeking to utilize EI in their work. We first provide an overview of the different conceptualizations of EI. We then provide a set of recommendations for practitioners and researchers regarding the most appropriate measures of EI for a range of different purposes. We provide guidance both on how to select and use different measures of EI. We conclude with a comprehensive review of the major measures of EI in terms of factor structure, reliability, and validity.
Global recognition of climate change and its predicted consequences has created the need for practical management strategies for increasing the ability of natural ecosystems to capture and store ...atmospheric carbon. Mangrove forests, saltmarshes and seagrass meadows, referred to as blue carbon ecosystems (BCEs), are hotspots of atmospheric CO2 storage due to their capacity to sequester carbon at a far higher rate than terrestrial forests. Despite increased effort to understand the mechanisms underpinning blue carbon fluxes, there has been little synthesis of how management activities influence carbon stocks and greenhouse gas (GHG) fluxes in BCEs. Here, we present a global meta‐analysis of 111 studies that measured how carbon stocks and GHG fluxes in BCEs respond to various coastal management strategies. Research effort has focused mainly on restoration approaches, which resulted in significant increases in blue carbon after 4 years compared to degraded sites, and the potential to reach parity with natural sites after 7–17 years. Lesser studied management alternatives, such as sediment manipulation and altered hydrology, showed only increases in biomass and weaker responses for soil carbon stocks and sequestration. The response of GHG emissions to management was complex, with managed sites emitting less than natural reference sites but emitting more compared to degraded sites. Individual GHGs also differed in their responses to management. To date, blue carbon management studies are underrepresented in the southern hemisphere and are usually limited in duration (61% of studies <3 years duration). Our meta‐analysis describes the current state of blue carbon management from the available data and highlights recommendations for prioritizing conservation management, extending monitoring time frames of BCE carbon stocks, improving our understanding of GHG fluxes in open coastal systems and redistributing management and research effort into understudied, high‐risk areas.
We present a global meta‐analysis of that assessed the response of blue carbon stocks and greenhouse gas fluxes in mangroves, saltmarsh and seagrass meadows to various coastal management strategies. Restoration, sediment manipulation and altered hydrology management show positive effects globally for degraded sites (mainly for biomass); however, the variance of responses and the time frames estimated by our models for carbon stock parity with natural sites (e.g. 7–17 years for restoration) suggest conservation management should be prioritized. Deficiencies in geographical distribution and time frame of studies containing empirical data are identified to advise future blue carbon management assessments.
Arsenic biotransformation mediated by gut microbiota can affect arsenic bioavailability and microbial community. Arsenic species, arsenic biotransformation genes (ABGs), and the composition of gut ...microbial community were characterized after the earthworm Metaphire sieboldi was cultured in soils spiked with different arsenic concentrations. Arsenite (As(III)) was the major component in the earthworm gut, whereas arsenate (As(V)) was predominant in the soil. A total of 16 ABGs were quantified by high-throughput quantitative polymerase chain reaction (HT-qPCR). Genes involved in arsenic redox and efflux were predominant in all samples, and the abundance of ABGs involved in arsenic methylation and demethylation in the gut was very low. These results reveal that the earthworm gut can be a reservoir of microbes with the capability of reducing As(V) and extruding As(III) but with little methylation of arsenic. Moreover, gut microbial communities were dominated by Actinobacteria, Firmicutes, and Proteobacteria at the phylum level and were considerably different from those in the surrounding soil. Our work demonstrates that exposure to As(V) disturbs the gut microbiota of earthworms and provides some insights into arsenic biotransformation in the earthworm gut.
PDF
