Pharmacologically active compounds with preferential cytotoxic activity for senescent cells, known as senolytics, can ameliorate or even revert pathological manifestations of senescence in numerous ...preclinical mouse disease models, including cancer models. However, translation of senolytic therapies to human disease is hampered by their suboptimal specificity for senescent cells and important toxicities that narrow their therapeutic windows. We have previously shown that the high levels of senescence‐associated lysosomal β‐galactosidase (SA‐β‐gal) found within senescent cells can be exploited to specifically release tracers and cytotoxic cargoes from galactose‐encapsulated nanoparticles within these cells. Here, we show that galacto‐conjugation of the BCL‐2 family inhibitor Navitoclax results in a potent senolytic prodrug (Nav‐Gal), that can be preferentially activated by SA‐β‐gal activity in a wide range of cell types. Nav‐Gal selectively induces senescent cell apoptosis and has a higher senolytic index than Navitoclax (through reduced activation in nonsenescent cells). Nav‐Gal enhances the cytotoxicity of standard senescence‐inducing chemotherapy (cisplatin) in human A549 lung cancer cells. Concomitant treatment with cisplatin and Nav‐Gal in vivo results in the eradication of senescent lung cancer cells and significantly reduces tumour growth. Importantly, galacto‐conjugation reduces Navitoclax‐induced platelet apoptosis in human and murine blood samples treated ex vivo, and thrombocytopenia at therapeutically effective concentrations in murine lung cancer models. Taken together, we provide a potentially versatile strategy for generating effective senolytic prodrugs with reduced toxicities.
We have developed a galactose‐conjugated derivative of Navitoclax (Nav‐Gal) with a broad‐spectrum senolytic activity. We show that Nav‐Gal efficiently kills chemotherapy‐induced senescent cells in xenografts and orthotopic in vivo models of NSCLC, resulting in impaired tumour progression. Importantly, our prodrug prevents Navitoclax‐induced platelet apoptosis in human samples and murine models. In summary, we provide a potentially versatile strategy for generating effective senolytic prodrugs with reduced toxicities.
The purpose of this study is to determine the effects of low-dose radiation on fibroblast cells irradiated by spectrally and dosimetrically well-characterized soft x-rays. To achieve this, a new cell ...culture x-ray irradiation system was designed. This system generates characteristic fluorescent x-rays to irradiate the cell culture with x-rays of well-defined energies and doses. 3T3 fibroblast cells were cultured in cups with Mylar® surfaces and were irradiated for one hour with characteristic iron (Fe) K x-ray radiation at a dose rate of approximately 550 μGy/hr. Cell proliferation, total protein analysis, flow cytometry, and cell staining were performed on fibroblast cells to determine the various effects caused by the radiation. Irradiated cells demonstrated increased proliferation and protein production compared to control samples. Flow cytometry revealed that a higher percentage of irradiated cells were in the G0/G1 phase of the cell cycle compared to control counterparts, which is consistent with other low-dose studies. Cell staining results suggest that irradiated cells maintained normal cell functions after radiation exposure, as there were no qualitative differences between the images of the control and irradiated samples. The result of this study suggest that low-dose soft x-ray radiation might cause an initial pause, followed by a significant increase, in proliferation. An initial "pause" in cell proliferation could be a protective mechanism of the cells to minimize DNA damage caused by radiation exposure. The new cell irradiation system developed here allows for unprecedented control over the properties of the x-rays given to the cell cultures. This will allow for further studies on various cell types with known spectral distribution and carefully measured doses of radiation, which may help to elucidate the mechanisms behind varied cell responses to low-dose x-rays reported in the literature.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The assassination of Julius Caesar in 44 BCE triggered a power struggle that ultimately ended the Roman Republic and, eventually, the Ptolemaic Kingdom, leading to the rise of the Roman Empire. ...Climate proxies and written documents indicate that this struggle occurred during a period of unusually inclement weather, famine, and disease in the Mediterranean region; historians have previously speculated that a large volcanic eruption of unknown origin was the most likely cause. Here we show using well-dated volcanic fallout records in six Arctic ice cores that one of the largest volcanic eruptions of the past 2,500 y occurred in early 43 BCE, with distinct geochemistry of tephra deposited during the event identifying the Okmok volcano in Alaska as the source. Climate proxy records show that 43 and 42 BCE were among the coldest years of recent millennia in the Northern Hemisphere at the start of one of the coldest decades. Earth system modeling suggests that radiative forcing from this massive, high-latitude eruption led to pronounced changes in hydroclimate, including seasonal temperatures in specific Mediterranean regions as much as 7 °C below normal during the 2 y period following the eruption and unusually wet conditions. While it is difficult to establish direct causal linkages to thinly documented historical events, the wet and very cold conditions from this massive eruption on the opposite side of Earth probably resulted in crop failures, famine, and disease, exacerbating social unrest and contributing to political realignments throughout the Mediterranean region at this critical juncture of Western civilization.
Limited knowledge of the distribution, abundance, and habitat associations of migratory species hinders effective conservation actions. We use Neotropical migratory birds as a model group to compare ...approaches to prioritize land conservation needed to support ≥30% of the global abundances of 117 species. Specifically, we compare scenarios from spatial optimization models to achieve conservation targets by: 1) area requirements for conserving >30% abundance of each species for each week of the year independently vs. combined; 2) including vs. ignoring spatial clustering of species abundance; and 3) incorporating vs. avoiding human-dominated landscapes. Solutions integrating information across the year require 56% less area than those integrating weekly abundances, with additional reductions when shared-use landscapes are included. Although incorporating spatial population structure requires more area, geographical representation among priority sites improves substantially. These findings illustrate that globally-sourced citizen science data can elucidate key trade-offs among opportunity costs and spatiotemporal representation of conservation efforts.
Lead pollution in Arctic ice reflects midlatitude emissions from ancient lead–silver mining and smelting. The few reported measurements have been extrapolated to infer the performance of ancient ...economies, including comparisons of economic productivity and growth during the Roman Republican and Imperial periods. These studies were based on sparse sampling and inaccurate dating, limiting understanding of trends and specific linkages. Here we show, using a precisely dated record of estimated lead emissions between 1100 BCE and 800 CE derived from subannually resolved measurements in Greenland ice and detailed atmospheric transport modeling, that annual European lead emissions closely varied with historical events, including imperial expansion, wars, and major plagues. Emissions rose coeval with Phoenician expansion, accelerated during expanded Carthaginian and Roman mining primarily in the Iberian Peninsula, and reached a maximum under the Roman Empire. Emissions fluctuated synchronously with wars and political instability particularly during the Roman Republic, and plunged coincident with two major plagues in the second and third centuries, remaining low for >500 years. Bullion in silver coinage declined in parallel, reflecting the importance of lead–silver mining in ancient economies. Our results indicate sustained economic growth during the first two centuries of the Roman Empire, terminated by the second-century Antonine plague.
Progression to exudative 'wet' age-related macular degeneration (exAMD) is a major cause of visual deterioration. In patients diagnosed with exAMD in one eye, we introduce an artificial intelligence ...(AI) system to predict progression to exAMD in the second eye. By combining models based on three-dimensional (3D) optical coherence tomography images and corresponding automatic tissue maps, our system predicts conversion to exAMD within a clinically actionable 6-month time window, achieving a per-volumetric-scan sensitivity of 80% at 55% specificity, and 34% sensitivity at 90% specificity. This level of performance corresponds to true positives in 78% and 41% of individual eyes, and false positives in 56% and 17% of individual eyes at the high sensitivity and high specificity points, respectively. Moreover, we show that automatic tissue segmentation can identify anatomical changes before conversion and high-risk subgroups. This AI system overcomes substantial interobserver variability in expert predictions, performing better than five out of six experts, and demonstrates the potential of using AI to predict disease progression.
Fast negative breakdown in thunderstorms Tilles, Julia N; Liu, Ningyu; Stanley, Mark A ...
Nature communications,
04/2019, Letnik:
10, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Thunderstorms are natural laboratories for studying electrical discharges in air, where the vast temporal, spatial, and energy scales available can spawn surprising phenomena that reveal deficiencies ...in our understanding of dielectric breakdown. Recent discoveries, such as sprites, jets, terrestrial gamma ray flashes, and fast positive breakdown, highlight the diversity of complex phenomena that thunderstorms can produce, and point to the possibility for electrical breakdown/discharge mechanisms beyond dielectric breakdown theory based mainly on laboratory experiments. Here we present one such confounding discovery, termed fast negative breakdown, that does not fit with our current understanding of dielectric breakdown. Our adaptation of radio astronomy imaging techniques to study extremely transient lightning-associated events confirms that electrical breakdown in thunderstorms can begin with oppositely-directed fast breakdown of negative polarity, similar and in addition to fast positive breakdown expected from conventional dielectric theory and recent observations. The discovery of fast negative breakdown calls for an addendum to the physical description of electrical discharges in air.
The human protein kinome comprises 535 proteins that, with the exception of approximately 50 pseudokinases, control intracellular signaling networks by catalyzing the phosphorylation of multiple ...protein substrates. While a major research focus of the last 30 years has been cancer-associated Tyr and Ser/Thr kinases, over 85% of the kinome has been identified to be dysregulated in at least one disease or developmental disorder. Despite this remarkable statistic, for the majority of protein kinases and pseudokinases, there are currently no inhibitors progressing toward the clinic, and in most cases, details of their physiologic and pathologic mechanisms remain at least partially obscure. By curating and annotating data from the literature and major public databases of phosphorylation sites, kinases, and disease associations, we generate an unbiased resource that highlights areas of unmet need within the kinome. We discuss strategies and challenges associated with characterizing catalytic and noncatalytic outputs in cells, and describe successes and new frontiers that will support more comprehensive cancer-targeting and therapeutic evaluation in the future.
Lead pollution in Arctic ice reflects large-scale historical changes in midlatitude industrial activities such as ancient lead/silver production and recent fossil fuel burning. Here we used ...measurements in a broad array of 13 accurately dated ice cores from Greenland and Severnaya Zemlya to document spatial and temporal changes in Arctic lead pollution from 200 BCE to 2010 CE, with interpretation focused on 500 to 2010 CE. Atmospheric transport modeling indicates that Arctic lead pollution was primarily from European emissions before the 19th-century Industrial Revolution. Temporal variability was surprisingly similar across the large swath of the Arctic represented by the array, with 250- to 300-fold increases in lead pollution observed from the Early Middle Ages to the 1970s industrial peak. Superimposed on these exponential changes were pronounced,multiannual to multidecadal variations, marked by increases coincident with exploitation of new mining regions, improved technologies, and periods of economic prosperity; and decreases coincident with climate disruptions, famines, major wars, and plagues. Results suggest substantial overall growth in lead/silver mining and smelting emissions—and so silver production—from the Early through High Middle Ages, particularly in northern Europe, with lower growth during the Late Middle Ages into the Early Modern Period. Near the end of the second plague pandemic (1348 to ∼1700 CE), lead pollution increased sharply through the Industrial Revolution. North American and European pollution abatement policies have reduced Arctic lead pollution by >80% since the 1970s, but recent levels remain ∼60-fold higher than at the start of the Middle Ages.
Multiple, independent time markers are essential to correlate sediment and ice cores from the terrestrial, marine and glacial realms. These records constrain global paleoclimate reconstructions and ...inform future climate change scenarios. In the Northern Hemisphere, sub-visible layers of volcanic ash (cryptotephra) are valuable time markers due to their widespread dispersal and unique geochemical fingerprints. However, cryptotephra are not as widely identified in the Southern Hemisphere, leaving a gap in the climate record, particularly during the Last Glacial Maximum (LGM). Here we report the first identification of New Zealand volcanic ash in Antarctic ice. The Oruanui supereruption from Taupo volcano (25,580 ± 258 cal. a BP) provides a key time marker for the LGM in the New Zealand sector of the SW Pacific. This finding provides a high-precision chronological link to mid-latitude terrestrial and marine sites, and sheds light on the long-distance transport of tephra in the Southern Hemisphere. As occurred after identification of the Alaskan White River Ash in northern Europe, recognition of ash from the Oruanui eruption in Antarctica dramatically increases the reach and value of tephrochronology, providing links among climate records in widely different geographic areas and depositional environments.
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