Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacological inhibitor of DNA-PK, M3814, potentiates radiotherapy and 1 regresses human tumors in mouse models 2

Physical and chemical DNA-damaging agents are used widely in the treatment of 46 cancer. Double-strand break (DSB) lesions in DNA are the most deleterious form of 47 damage and, if left unrepaired, can effectively kill cancer cells. DNA-dependent 48 protein kinase (DNA-PK) is a critical component of non-homologous end joining 49 (NHEJ), one of the two major pathways for DSB repair. Whilst DNA-PK has been 50 considered an attractive target for cancer therapy, the development of 51 pharmacological DNA-PK inhibitors for clinical use has been lagging. Here, we report 52 the discovery and characterization of a potent, selective, and orally bioavailable DNA- 53 PK inhibitor, M3814, and provide in vivo proof of principle for DNA-PK inhibition as a 54 novel approach to combination radiotherapy. M3814 potently inhibits DNA-PK 55 catalytic activity and sensitizes multiple cancer cell lines to ionizing radiation (IR) and 56 DSB-inducing agents. Inhibition of DNA-PK autophosphorylation in cancer cells or 57 xenograft tumors led to an increased number of persistent DSBs. Oral administration 58 of M3814 to two xenograft models of human cancer, using a clinically established 6- 59 week fractionated radiation schedule, strongly potentiated the antitumor activity of IR 60 and led to complete tumor regression at non-toxic doses. Our results strongly support 61 DNA-PK inhibition as a novel approach for the combination radiotherapy of cancer. 62 M3814 is currently under investigation in combination with radiotherapy in clinical 63 trials. broadly reduces the viability of cell lines and synergistically enhances the activity of DNA DSB-inducing drugs.
Semidirect radiative forcing of internal mixed black carbon cloud droplet and its regional climatic effect over China

[1] Black carbon (BC) is one of the most important atmospheric aerosols. It can exert a positive radiative forcing by absorbing solar radiation and a negative radiative forcing by acting as cloud condensation nuclei (CCN) at the top of the atmosphere (TOA). Furthermore, cloud droplets with BC can absorb more solar radiation and reduce their single-scattering albedo (SSA), leading to a positive cloud radiative forcing (SSA forcing) at TOA. Here we include such a process into the coupled modeling system (RegCCMS) which consists of a regional climate model (RegCM3) and a tropospheric atmosphere chemistry model (TACM) to investigate BC loading, SSA forcing, and its climatic responses in different seasons over China. The year 2003 was selected as the base year for this study. Results show high BC loadings in Sichuan, Hebei, and Shandong provinces with weak seasonal variations. The national average SSA forcing due to the cloud droplets absorption is 0.04, 0.096, 0.085, and 0.056 W/m2 at TOA, while −0.05, −0.14, −0.12, and −0.077 W/m2 at the surface in January, April, July, and October, respectively. It can reach as much as 0.6 W/m2 at TOA and −0.8 W/m2 at the surface in the regions with high BC concentration and cloud cover. Numerical experiments indicate that internal mixed BC and cloud droplet can absorb more solar radiation, then heat the air, hence reducing the cloud cover and increasing vertical velocity. On the other hand, more solar absorption due to mixture droplets can alter atmospheric and hydrologic cycle, which consequently changes the distribution of cloud cover and eventually affects surface air temperature, precipitation, and solar radiation. Given an above 90% confidence level of statistical significance of linear correlation between SSA forcing and climate changes, surface air temperature changes for 4 months vary from −0.0022 to +0.0103 K and precipitation changes range from −0.0047 in January to 0.029 mm/d in April. These changes show an extremely large seasonal variation; so do those of cloud amount (Max: −0.066%) and solar flux (Max: 0.21 W/m2). Owing to the small SSA forcing, its climatic responses are easily masked by internal model variability in summer season, especially for precipitation and cloud. Even so, small SSA forcing in colder seasons may lead to noticeable local surface drought or cooling. For example, precipitation decreases in Yangtze River Basin reaching 1.2 mm/d in October; surface air temperatures decrease by 0.2 to 0.4 K in east China in April. It is obvious that SSA forcing and its climate responses are weaker compared to BC direct, indirect, and semidirect effects. However, it does have nonnegligible influence on regional climate changes over China.
Latitudinal Range Variation of Trees in the United States: A Reanalysis of the Applicability of Rapoport's Rule*

Abstract In 1975 E. H. Rapoport described a pattern of increasing latitudinal range sizes for organisms with increasing latitude, a pattern that is now known as Rapoport's rule. The universal applicability of Rapoport's rule has been long contested, making it one of the more controversial biogeographic “rules. ” This study aims to reassess the applicability of Rapoport's rule to U.S. tree species. Data presented here suggest that Rapoport's rule does indeed apply to most tree taxa within the United States, but may be taxon specific. In addition, data presented here suggest that tree range patterns consistent with Rapoport's rule in the United States are not restricted to high latitudes and are not the result of a “boundedness effect” but may be intimately linked with the glacial history and physical geography of North America. The analyses conducted here are intended to emphasize the utility of such biogeographic rules even if they are not universally applicable and should, in turn, only be considered biogeographic patterns.
Transmission Dynamics and Microevolution of Neisseria meningitidi s During Carriage and Invasive Disease in High School Students in Georgia and Maryland, 2006–2007

sequence typing was used to compare allelic profiles, and direct read mapping was used to study strain evolution. Results. Among 188 N. meningitidis culture–positive students, 98 (52.1%) were N. meningitidis culture positive at 2 or 3 sam-plings. Most students who were positive at >1 sampling (98%) had persistence of a single strain. More than a third of students carried isolates that were highly genetically related to isolates from other students in the same school, and occasional transmission within the same county was also evident. The major pilin subunit gene, pilE, was the most variable gene, and no carrier had identical pilE sequences at different time points. Conclusion. We found strong evidence of local meningococcal transmission at both the school and county levels. Allelic variation within genes encoding bacterial surface structures, particularly pilE , was common.
The Adaptive Nature of Eye-movements in Linguistic Tasks: How Payoff and Architecture Shape Speed-accuracy Tradeoffs

We explore the idea that eye-movement strategies in reading are precisely adapted to the joint constraints of task structure, task payoff, and processing architecture. We present a model of saccadic control that separates a parametric control policy space from a parametric machine architecture, the latter based on a small set of assumptions derived from research on The eye-control model is embedded in a decision architecture (a machine and policy space) that is capable of performing a simple linguistic task integrating information across saccades. Model predictions are derived by jointly optimizing the control of eye-movements and task decisions under payoffs that quantitatively express different desired speed-accuracy tradeoffs. The model yields distinct eye-movement predictions for the same task under different payoffs, including single-fixation durations, frequency effects, accuracy effects, and list position effects, and their modulation by task payoff. The predictions are compared to—and found to accord with—eye-movement data obtained from human participants performing the same task under the same payoffs, but are found not to accord as well when the assumptions concerning payoff optimization and processing architecture are varied. These results extend work on rational analysis of oculomotor control and adaptation of reading strat-1973) by providing evidence for adaptation at low levels of saccadic control that is shaped by quantitatively varying task demands and the dynamics of processing architecture.
Enhancement of the consistency of MODIS thin cirrus with cloud phase by adding 1.6 μm reflectance

Optically thin cirrus derived from the Moderate‐resolution Imaging Spectroradiometer (MODIS) instrument is examined in connection with its cloud phase (ice crystal or liquid droplet) for quasi‐single layer thin cirrus (either single‐layer thin cirrus or thin cirrus overlying low‐level thin clouds) over water surface conditions. Analysing 142 MODIS data samples during the period 1–16 March 2000, it is found that only about 20% of MODIS thin cirrus having a total‐column cloud optical depth less than 2.0 was detected as ice phase. In the present study, MODIS cloud phase datasets are newly reproduced by adding the 1.6 μm reflectance to an existing infrared trispectral algorithm of MODIS which used the 8.7, 11 and 12 mm bands. The percentage of ice phase in the thin cirrus is estimated at about 80% when new cloud phase is incorporated. The increase is found for all regions, in particular in mid‐latitudes.
Processes affecting transfer of sediment and colloids, with associated phosphorus, from intensively farmed grasslands: tracing sediment and organic matter

S. J. Granger,1* R. Bol,2 P. J. Butler,2 P. M. Haygarth,1 P. Naden,3 G. Old,3 P. N. Owens4,5 and B. P. G. Smith3 1 Nutrient Flows and Systems Modelling Team, Institute of Grassland and Environmental Research (IGER), North Wyke Research Station, Okehampton, Devon, EX20 2SB, UK 2 Cross Institute Programme for Sustainable Soil Function (SoilCIP), Institute of Grassland and Environmental Research (IGER), North Wyke Research Station, Okehampton, Devon, EX20 2SB, UK 3 Centre for Ecology and Hydrology (CEH), Wallingford, OX10 8BB, UK 4 National Soil Resources Institute, Cranfield University, North Wyke Research Station, Okehampton, Devon EX20 2SB, UK 5 Environmental Sciences Program, University of Northern British Columbia, Prince George, British Columbia, V2N 4Z9, Canada
Complications maternelles des extractions instrumentales

Résumé L’extraction instrumentale majore significativement le risque de déchirure du sphincter anal par rapport à la voie basse spontanée, notamment lorsqu’une application haute de l’instrument, une présentation en variété postérieure et/ou une macrosomie sont associées (NP2). Les risques de déchirure vaginale, d’hémorragie du post-partum et de rétention urinaire aiguë semblent être augmentés par rapport à la voie basse spontanée (NP3). Il n’existe pas de preuve qu’un type de forceps soit plus délétère qu’un autre. Les différentes ventouses (souples, rigides et à usage unique) comportent les mêmes risques maternels (NP2). Le risque d’incontinence anale dans l’année qui suit un accouchement par voie basse est associé à la réalisation d’une extraction instrumentale, notamment d’un forceps (NP2). De même, celle-ci semble majorer le risque de lésion occulte du sphincter anal, quel que soit l’instrument (NP2). L’extraction instrumentale ne semble pas être associée au risque d’incontinence urinaire du post-partum ou à la survenue d’un prolapsus génital par rapport à la voie basse spontanée (NP2). Par contre, elle majore les risques de douleurs périnéales, de dyspareunie et de troubles sexuels du post-partum par rapport à la voie basse spontanée, et ce d’autant plus qu’il existe des déchirures périnéales (NP3). © 2008 Elsevier Masson SAS. Tous droits réservés.
A decade of oceanographic variability in summertime near Elephant Island, Antarctica

The oceanography of near-surface (to 750 m) summertime waters surrounding the Elephant Island area of the South Shetland Islands has been surveyed each year from 1990 to 1999 as part of the U.S. Antarctic Marine Living Resources (AMLR) program. Using data from a grid of conductivity-temperature-depth stations occupied twice each summer and surface meteorological data collected continuously in the survey area, the mean (and annual departures from the mean) hydrography, circulation, and overlying wind field have been determined. The area is an important krill fishing ground and includes several water mass zones and a major frontal boundary. Differences between middle and late summer (“seasonal”) conditions and interannual variability have been investigated. The mean summer condition is quite representative of conditions encountered in each of the 10 years, and little change occurs from middle to late summer, other than a warming of Antarctic Surface Water, including the Winter Water temperature minimum at 100 m, but there is no discernible trend from middle to late summer at the depth of the Circumpolar Deep Water. Interannual variability of sea temperature, winds, and sea level pressure as measured during these surveys showed no correlation with a sea ice index and a recently devised pressure index, the Drake Passage Oscillation Index (DPOI) [Naganobu et al., 1999], despite the correlations found in that study between AMLR chlorophyll a and krill recruitment indices, sea ice, and the DPOI. No correlation was found between DPOI and annual summertime sea temperature, wind, and surface pressure anomalies in the survey area. The implication is that global-scale climatic oscillations with periodicities measured in years may not be adequately detected by small-scale oceanographic surveys even though the surveys may extend over several years unless the surveys are specifically designed for that purpose.
Science requisites for cumulative effects assessment for wetlands

Wetland habitat continues to be lost to cumulative effects of development on the landscape. Part of the problem is that there currently exists only limited guidance as to how to use the existing scientific tools, conceptual frameworks and guidance documents to advance cumulative effects assessment (CEA) from the project scale to the broader regional scale at which land-use planning occurs. To strengthen CEA science for wetlands there are three minimum requirements: (1) understand the baseline science of wetland functions; (2) delineate the primary drivers (anthropogenic and natural) of disturbance; and (3) develop the science to link drivers to changes in wetland function in an interactive, synergistic and cumulative way. The paper concludes by identifying ways in which the state of CEA science and management of wetlands could be improved.
Development and Validation of New HPLC Method for Simultaneous Estimation of L-Lysine Hydrochloride and L-Carnitine L-Tartrate in Pharmaceutical Dosage Form

Copyright: © 2014 Qadir MA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Development and Validation of New HPLC Method for Simultaneous Estimation of L-Lysine Hydrochloride and L-Carnitine L-Tartrate in Pharmaceutical Dosage Form
A Method for Automatic Detection and Classification of Stroke from Brain Ct Images

— Computed tomographic (CT) images are widely used in the diagnosis of stroke. In this paper, we present an automated method to detect and classify an abnormality into acute infarct, chronic infarct and hemorrhage at the slice level of non-contrast CT images. The proposed method consists of three main steps: image enhancement, detection of mid-line symmetry and classification of abnormal slices. A windowing operation is performed on the intensity distribution to enhance the region of interest. Domain knowledge about the anatomical structure of the skull and the brain is used to detect abnormalities in a rotation-and translation-invariant manner. A two-level classification scheme is used to detect abnormalities using features derived in the intensity and the wavelet domain. The proposed method has been evaluated on a dataset of 15 patients (347 image slices). The method gives 90% accuracy and 100% recall in detecting abnormality at patient level; and achieves an average precision of 91% and recall of 90% at the slice level.
Proliferation and AKT Activity Biomarker Analyses after Capivasertib (AZD5363) Treatment of Patients with ER þ Invasive Breast Cancer (STAKT) A

◥ Purpose: The STAKT study examined short-term exposure (4.5 days) to the oral selective pan-AKT inhibitor capivasertib (AZD5363) to determine if this drug can reach its therapeutic target in suf ﬁ cient concentration to signi ﬁ cantly modulate key biomarkers of the AKT pathway and tumor proliferation. Methods: STAKT was a two-stage, double-blind, randomized, placebo-controlled, “ window-of-opportunity ” study in patients with newly diagnosed ER þ invasive breast cancer. Stage 1 assessed capivasertib 480 mg b.i. d. (recommended monotherapy dose) and placebo, and stage 2 assessed capivasertib 360 and 240 mg b.i. d. Primary endpoints were changes from baseline in AKT pathway markers pPRAS40, pGSK3 b , and proliferation protein Ki67. Pharmacologic and pharmacodynamic properties were analyzed from blood sampling, and tolerability by adverse-event monitoring. Results: After 4.5 days ’ exposure, capivasertib 480 mg b.i. d. ( n ¼ 17) producedsigni ﬁ cantdecreases frombaselineversus placebo ( n ¼ 11) in pGSK3 b (H-score absolute change: (cid:2) 55.3, P ¼ 0.006) and pPRAS40 ( (cid:2) 83.8, P < 0.0001), and a decrease in Ki67 (absolute change in percentage positive nuclei: (cid:2) 9.6%, P ¼ 0.031). Signi ﬁ cant changes also occurred in secondary signaling biomarker pS6 ( (cid:2) 42.3, P ¼ 0.004), while pAKT (and nuclear FOXO3a) also increased in accordance with capivasertib's mechanism (pAKT: 81.3, P ¼ 0.005). Atdosesof360mgb.i. d. ( n ¼ 5)and240mgb.i. d. ( n ¼ 6),changesin primary and secondary biomarkers were also observed, albeit of smaller magnitude. Biomarker modulation was dose and concentration dependent, and no new safety signals were evident. Conclusions: Capivasertib rapidly key of and decreases proliferation marker AKT-dependent breast effect of capivasertib on selected tumor and cell proliferation biomarkers, the PD properties of the dose – and exposure – response relationship, and tolerability from short-term exposure in patients with breast cancer.
Special Submission GAPS IN KNOWLEDGE RELEVANT TO THE “GUIDELINES FOR LIMITING EXPOSURE TO TIME-VARYING ELECTRIC AND MAGNETIC FIELDS (1 HZ–100 KHZ)”

Sources of low-frequency fields are widely found in modern society. All wires or devices carrying or using electricity generate extremely low frequency (ELF) electric fields (EFs) and magnetic fields (MFs), but they decline rapidly with distance to the source. High magnetic flux densities are usually found in the vicinity of power lines and close to equipment using strong electrical currents, but can also be found in buildings with unbalanced return currents, or indoor transformer stations. For decades, epidemiological as well as experimental studies have addressed possible health effects of exposure to ELF-MFs. The main goal of ICNIRP is to protect people and the environment from detrimental exposure to all forms of non-ionizing radiation (NIR). To this end, ICNIRP provides advice and guidance by developing and disseminating exposure guidelines based on the available scientific research. Research in the low-frequency range began more than 40 years ago, and there is now a large body of literature available on which ICNIRP set its protection guidelines. A review of the literature has been carried out to identify possible relevant knowledge gaps, and the aim of this statement is to describe data gaps in research that would, if addressed, assist ICNIRP in further developing guidelines and setting revised recommendations on limiting exposure to electric and magnetic fields. It is articulated in two parts: the main document, which reviews the science related to LF data gaps, and the annex, which explains the methodology used to identify the data gaps. Health Phys. 118(5):533–542; 2020
ECONOMIC CRISIS, HEALTH SYSTEMS AND HEALTH IN EUROPE: IMPACT AND IMPLICATIONS FOR POLICY

How have health systems in Europe responded to the crisis? How have these responses affected health system performance and population health? And what are the implications of this experience for health systems facing economic and other forms of shock in the future? This new document summarizes the findings of a joint study by WHO Europe and the Observatory analyzing the impact of health policy responses to the crisis in Europe from 2008 to 2013. It is a key part of a wider initiative to monitor the effects of the crisis on health systems and health, to identify the policies most likely to sustain the performance of health systems facing fiscal pressure and to gain insight into the political economy of implementing reforms in a crisis. The study was supported by the Norwegian Directorate of Health and the UK Department for International Development. It will be published by the Open University Press in January 2015 and will be downloadable from this site soon afterwards.
Culturally Modified Human Remains Recovered from an Earth-oven Interment on Waya Island, Fiji

The incomplete skeletal remains of a young adolescent (10-12 years of age) were recovered from the uppermost layer of an earth-oven at the Qaranicagi Site (Y2-39), Waya Island, Fiji. Analysis of the remains revealed minimal fire or heat alteration. Cut marks are distributed across several elements and suggest at least partial butchering of the individual.
Adaptive immune disorders Review in hypertension and heart failure: focusing onT-cell subset activation and clinical implications

Journal of Hypertension 2020, 38:1878–1889 Department of Cardiology, Yanbian University Hospital, Juzijie, Yanji, Jilin Province, China, Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan and State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China