Miracle-dz/UniFAR-FTUs huggingface dataset:
Evolutionary dynamics of cancer in response to targeted combination therapy

In solid tumors, targeted treatments can lead to dramatic regressions, but responses are often short-lived because resistant cancer cells arise. The major strategy proposed for overcoming resistance is combination therapy. We present a mathematical model describing the evolutionary dynamics of lesions in response to treatment. We first studied 20 melanoma patients receiving vemurafenib. We then applied our model to an independent set of pancreatic, colorectal, and melanoma cancer patients with metastatic disease. We find that dual therapy results in long-term disease control for most patients, if there are no single mutations that cause cross-resistance to both drugs; in patients with large disease burden, triple therapy is needed. We also find that simultaneous therapy with two drugs is much more effective than sequential therapy. Our results provide realistic expectations for the efficacy of new drug combinations and inform the design of trials for new cancer therapeutics. DOI: http://dx.doi. org/10.7554/eLife.00747. 001
Slip‐parallel seismic lineations on the Northern Hayward Fault, California

A high‐resolution relative earthquake location procedure is used to image the fine‐scale seismicity structure of the northern Hayward fault, California. The seismicity defines a narrow, near‐vertical fault zone containing horizontal alignments of hypocenters extending along the fault zone. The lineations persist over the 15‐year observation interval, implying the localization of conditions on the fault where brittle failure conditions are met. The horizontal orientation of the lineations parallels the slip direction of the fault, suggesting that they are the result of the smearing of frictionally weak material along the fault plane over thousands of years.
Concomitant Sleep Disorders Significantly Increase the Risk of Cardiovascular Disease in Patients with Psoriasis

Background The increased rates of cardiovascular morbidity and mortality in patients with psoriasis are not adequately explained by traditional risk factors. Whether concomitant sleep disorders (SDs) modify the risk of cardiovascular disease (CVD) in patients with psoriasis remains unknown. Methods Using the Taiwan National Health Insurance Research Database (NHIRD), we conducted a cohort study to investigate the association between concomitant SDs and CVD risk in patients with psoriasis. Data from 99,628 adults who received a psoriasis diagnosis during the period from 2004 to 2010 were analyzed. Cox proportional hazards regression analysis models were used to compare the risks of ischemic heart disease (IHD) and stroke between patients with and without SDs. Results Psoriasis patients with a concomitant SD had significantly higher risks of IHD (adjusted hazard ratio [aHR], 1.25; 95% confidence interval [CI], 1.22–1.28) and stroke (aHR, 1.24; 95% CI, 1.16–1.33) as compared with psoriasis patients without SDs. All psoriasis patient subgroups, including those with mild and severe psoriasis and those with and without arthritis, had increased HRs for IHD and stroke. The increases in IHD and stroke risks conferred by SDs were proportional to the dose of hypnotics used. The effect of SDs on the risks of IHD and stroke was greater in young adults than in middle-aged and older adults. Conclusions The risks of IHD and stroke were higher for psoriasis patients with SDs than for those without SDs. Clinicians should carefully evaluate CVD risk, particularly in young patients with psoriasis.
Comprehensive and Efficient Design Parameter Selection for Soft Error Resilient Processors via Universal Rules

Soft errors have been significantly degrading the reliability of current processors whose feature sizes and supply voltages are fast scaling down. In this paper, we propose two effective approaches to characterize processor reliability against soft errors at presilicon stage. By utilizing a rule search strategy named Patient Rule Induction Method (PRIM), we are capable of generating a set of selective rules on key design parameters. These rules quantify the design space subregion with the lowest effective soft error rate (SER), thus providing useful guidelines in designing reliable processors. Furthermore, we also propose to use Classification and Regression Trees (CART) to partition the design space into a number of small subregions each being associated with a representative SER value. This gives the processor designer a global view of the SER distribution, enabling a comprehensive analysis over the entire design space. More importantly, both approaches generate “universal” models whose effectiveness is validated with a set of test programs unseen to training. Compared to traditional application-specific design space studies, our models' cross-program capability can save great training effort in the era of multithreading. Finally, a case study on multiprocessors is performed to simultaneously balance multiple design metrics, including reliability, performance, and power.
Variations of Lateral Bedrock Erosion Rates Control Planation of Uplifting Folds in the Foreland of the Tian Shan, NW China

Fluvial planation surfaces, such as straths, commonly serve as recorders of climatic and tectonic changes and are formed by the lateral erosion of rivers, a process that remains poorly understood. Here we present a study of kilometer‐wide, fluvially eroded, low‐relief surfaces on rapidly uplifting folds in the foreland of the southwestern Tian Shan. A combination of field work, digital elevation model analysis, and dating of fluvial deposits reveals that despite an arid climate and rapid average rock‐uplift rates of 1–3 mm/yr, rivers cut extensive (>1–2 km wide) surfaces with typical height variations of <6 m over periods of >2–6 kyr. The extent of this “beveling” varies in space and time, such that different beveling episodes affect individual structures. Between times of planation, beveled surfaces are abandoned, incised, and deformed across the folds. In a challenge to models that link strath cutting and abandonment primarily to changes in river incision rates, we demonstrate that lateral erosion rates of antecedent streams crossing the folds have to vary by more than 1 order of magnitude to explain the creation of beveled platforms in the past and their incision at the present day. These variations do not appear to covary with climate variability and might be caused by relatively small (much less than an order of magnitude) changes in sediment or water fluxes. It remains uncertain in which settings variations in lateral bedrock erosion rates predominate over changes in vertical erosion rates. Therefore, when studying fluvial planation and strath terraces, variability of both lateral and vertical erosion rates should be considered.
A mix of apple pomace polysaccharide improves mitochondrial function and reduces oxidative stress in the liver of high‐fat diet‐induced obese mice

Scope: Apple pomace polysaccharides (APP), a free radical scavenger, is one of the major compounds derived from apple pomace. However, whether APP has beneficial effects on metabolic disorders is still unknown. Methods and results: In the present study, water‐soluble APP was isolated from the pomace of the locally abundant “Qinguan” apple and chemically characterized. Then, APP was orally administrated to high‐fat diet (HFD)‐induced obese mice. We found that APP significantly reduced HFD‐induced body weight gain and ameliorated HFD‐induced hepatic metabolic disorders and oxidative stress. In a palmitate‐loaded HepG2 cell model, APP protected the cells from palmitate‐induced insulin resistance and loss of viability by suppressing mitochondrial reactive oxygen species and rescuing mitochondrial respiratory function. Conclusion: Our work suggests that APP, a promising bioactive food component, successfully improved obesity‐associated hepatic metabolic disorder, most likely though the activation of hepatic mitochondrial function and the suppression of mitochondria oxidative stress.
Nitric Oxide Modulation of Neurally Induced Proximal Tubular Fluid Reabsorption in the Rat

This study investigated the role of NO in mediating the renal sympathetic nerve–mediated increases in proximal tubular fluid reabsorption (Jva). In inactin-anesthetized Wistar rats, renal sympathetic nerve stimulation (15 V, 2 ms) at 0.75 and 1.0 Hz did not change blood pressure or glomerular filtration rate but did decrease urine flow and sodium excretion in a frequency-related fashion by 40% to 50% at 1.0 Hz (both, P <0.01). Renal nerve stimulation in control animals increased Jva by 11% at 0.75 Hz (P <0.05) and 31% at 1.0 Hz (P <0.01). Intraluminal N&ohgr;-nitro-l-arginine methyl ester (L-NAME) resulted in a higher basal Jva (19%, P <0.05), and renal nerve stimulation had no effect on Jva. When L-NAME plus sodium nitroprusside was present intraluminally, however, there were frequency-dependent increases in Jva that were similar in pattern and magnitude to the control rats. Introduction of the relatively selective nNOS blocker 7-nitroindazole intraluminally, at 10−6 and 10−4 M, raised basal Jva by 18% and 24%, respectively (P <0.01), and renal nerve stimulation did not change Jva. Intraluminal aminoguanidine (10−4 M), a relatively selective iNOS blocker, did not affect basal Jva, which remained unchanged during renal nerve stimulation. These data are consistent with NO exerting a tonic inhibitory action on the basal levels of Jva, which, in part, is caused by NO generated by the nNOS isoform. Moreover, the findings have revealed that the presence of NO is necessary to ensure that renal nerves can stimulate fluid reabsorption by the proximal tubules, requiring NO generated from both nNOS and iNOS.
Expression of VCAM-1 in the normal and diseased kidney.

We have conducted an immunocytochemical analysis to investigate the presence of the recently described vascular cell adhesion molecule-1 (VCAM-1) in human kidney, using the anti-VCAM-1 monoclonal antibody 1.4C3. In normal control tissue VCAM-1 was present on some (but not all) parietal epithelial cells lining Bowman's capsule. Forty-nine of fifty clinical biopsy specimens were characterised by the additional presence of VCAM-1 on proximal tubular cells. This was most marked in biopsies of patients with interstitial nephritis or systemic vasculitis with crescentic nephritis, but was also observed in biopsies with minimal change, IgA or lupus nephropathy, or from patients with diabetic nephropathy, amyloid, or gout. Proximal tubule VCAM-1 correlated significantly with the number of transferrin-receptor-positive leukocytes (r = 0.607, p less than 0.0001) in the interstitium, but not with expression of HLA-DR by tubular cells. Surprisingly, VCAM-1 was not observed on vascular endothelial cells in these biopsies, even in the presence of a marked infiltrate; this contrasts with other tissues (e.g. skin and synovium). The presence of VCAM-1 on tubular cells in the inflamed kidney indicates the potential for these cells to interact with mononuclear cells, either as accessory cells or as cytotoxic targets. The unexpected absence of VCAM-1 in renal vascular endothelial cells suggests local differences in the endothelial cells of this organ.
Particulate Matter from Both Heavy Fuel Oil and Diesel Fuel Shipping Emissions Show Strong Biological Effects on Human Lung Cells at Realistic and Comparable In Vitro Exposure Conditions

Background Ship engine emissions are important with regard to lung and cardiovascular diseases especially in coastal regions worldwide. Known cellular responses to combustion particles include oxidative stress and inflammatory signalling. Objectives To provide a molecular link between the chemical and physical characteristics of ship emission particles and the cellular responses they elicit and to identify potentially harmful fractions in shipping emission aerosols. Methods Through an air-liquid interface exposure system, we exposed human lung cells under realistic in vitro conditions to exhaust fumes from a ship engine running on either common heavy fuel oil (HFO) or cleaner-burning diesel fuel (DF). Advanced chemical analyses of the exhaust aerosols were combined with transcriptional, proteomic and metabolomic profiling including isotope labelling methods to characterise the lung cell responses. Results The HFO emissions contained high concentrations of toxic compounds such as metals and polycyclic aromatic hydrocarbon, and were higher in particle mass. These compounds were lower in DF emissions, which in turn had higher concentrations of elemental carbon (“soot”). Common cellular reactions included cellular stress responses and endocytosis. Reactions to HFO emissions were dominated by oxidative stress and inflammatory responses, whereas DF emissions induced generally a broader biological response than HFO emissions and affected essential cellular pathways such as energy metabolism, protein synthesis, and chromatin modification. Conclusions Despite a lower content of known toxic compounds, combustion particles from the clean shipping fuel DF influenced several essential pathways of lung cell metabolism more strongly than particles from the unrefined fuel HFO. This might be attributable to a higher soot content in DF. Thus the role of diesel soot, which is a known carcinogen in acute air pollution-induced health effects should be further investigated. For the use of HFO and DF we recommend a reduction of carbonaceous soot in the ship emissions by implementation of filtration devices.
C-Band SAR Backscatter Evaluation of 2008 Gallipoli Forest Fire

The ability to quantify forest fire severity levels is of great importance for fire monitoring, management, and research. Optical observations have been found to be well suited to estimate the impact of fire on the forest canopy. In this letter, C-band VV polarization synthetic aperture radar (SAR) backscatter response to a forest fire was evaluated against burn severity estimated by the Landsat difference Normalized Burn Ratio (dNBR) products. It was observed that the difference between pre- and postfire back-scatters (ratios in power) increased with the dNBR index. Temporal evaluation of backscatter change with respect to various pre- and postfire conditions showed a noticeable sensitivity on the state of a burned stand and its local fire impact levels in wet conditions but, to a lesser degree, in dry conditions. A SAR approach that combines pre- and postfire backscattering could be used to quantify the fire impacts if the effects induced by geometry, weather, and other human activities are accounted for in the analysis.
Memory in multiple sclerosis is linked to glutamate concentration in grey matter regions

Objective Glutamate is the principal excitatory neurotransmitter and is involved in normal brain function. Cognitive impairment is common in multiple sclerosis (MS), and understanding its mechanisms is crucial for developing effective treatments. We used structural and metabolic brain imaging to test two hypotheses: (i) glutamate levels in grey matter regions are abnormal in MS, and (ii) patients show a relationship between glutamate concentration and memory performance. Methods Eighteen patients with relapsing-remitting MS and 17 healthy controls were cognitively assessed and underwent 1H-magnetic resonance spectroscopy at 3 T to assess glutamate levels in the hippocampus, thalamus, cingulate and parietal cortices. Regression models investigated the association between glutamate concentration and memory performance independently of magnetisation transfer ratio values and grey matter lesions withint he same regions, and whole-brain grey matter volume. Results Patients had worse visual and verbal memory than controls. A positive relationship between glutamate levels in the hippocampal, thalamic and cingulate regions and visuospatial memory was detected in patients, but not in healthy controls. Conclusions The relationship between memory and glutamate concentration, which is unique to MS patients, suggests the reliance of memory on glutamatergic systems in MS.
Binary and ternary particulated composites: UHMWPE/CACO3/HDPE

A study of the influence of employing ultrahigh molecular weight polyethylene (UHMWPE) on the toughness of CaCO3/high-density polyethylene (HDPE) composites was carried out. Binary and ternary HDPE-based composites with calcium carbonate in the range of 0–40% and UHMWPE in the range of 0–50% were produced by twin-screw extrusion followed by compression molding. From tensile and impact tests, it was found that increasing calcium carbonate content increased tensile modulus, but decreased tensile strength, strain at break, and impact resistance. The addition of UHMWPE helped to increase the strain at break and impact resistance of composites moderately without decreasing modulus or strength. The degree of toughening was found to increase with increasing UHMWPE content, but to decrease as the filler volume fraction was increased. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 75: 1503–1513, 2000
Pharmacologic methods to reduce perioperative bleeding

P erioperative bleeding is a clinical problem commonly faced by surgeons, anesthesiologists, and hematologists who manage trauma and surgical patients. Bleeding after surgery can be from multiple causes. Cardiac surgery with or without cardiopulmonary bypass (CPB) and mediastinal suctioning produces multiple hemostatic abnormalities, releases tissue factor, and activates the fibrinolytic cascade, all contributing to multiple hemostatic defects. Platelet (PLT)related defects have been shown to be the most important hemostatic abnormality after cardiac surgery. Furthermore, an increasing number of patients receive preoperative PLT inhibitors (i.e., clopidogrel) that may contribute to bleeding. Reducing blood product administration has important outcomes for blood inventory, blood costs, and overall health care costs. Pharmacologic approaches to reduce bleeding and transfusion needs have been extensively studied in cardiac and orthopedic surgery and are based on either preventing or reversing the defects associated with the coagulopathy. Surgical patients have the important advantage that pharmacologic approaches can be preemptively administered to prevent bleeding. Because in vivo coagulation depends on suitable PLT-fibrinogen interactions, fibrinolysis represents an important cause of bleeding. Thus, inhibiting fibrinolysis with either the lysine analogs e-aminocaproic acid (EACA) or tranexamic acid (TA) or with the broad-spectrum serine protease inhibitor aprotinin represents standard therapy. Although topical agents, such as fibrin sealants, have been successfully used in a variety of surgical procedures, few controlled clinical trials have been performed and scientific evidence supporting their use is still limited. This review will focus on major considerations in the evaluation and management of bleeding, and review the data on aprotinin including current perspectives and FDA communications.
Resolving Shell Nouns

Shell nouns, such as fact and problem, occur frequently in all kinds of texts. These nouns themselves are unspecific, and can only be interpreted together with the shell content. We propose a general approach to automatically identify shell content of shell nouns. Our approach exploits lexicosyntactic knowledge derived from the linguistics literature. We evaluate the approach on a variety of shell nouns with a variety of syntactic expectations, achieving accuracies in the range of 62% (baseline = 33%) to 83% (baseline = 74%) on crowd-annotated data.
Impact of diabetes on diagnostic delay for pulmonary tuberculosis in Beijing.

SETTING Delays in the diagnosis of pulmonary tuberculosis (PTB) increase the risk of transmission and severity of the disease. Little information is available on PTB patients with diabetes mellitus (DM). OBJECTIVES To examine the impact of DM on delays in diagnosing PTB and the effect of diagnostic delay on the clinical presentation of PTB among patients in Beijing, China. DESIGN In a cross-sectional study conducted in two PTB dispensaries of Beijing, all confirmed PTB patients were screened for DM. Data relating to diagnostic delay and clinical presentation of PTB were collected and analysed. RESULTS Of 1126 PTB patients selected, 182 (16.2%) were identified as having DM. The median delay for PTB patients with DM (25 days) was significantly higher than that of PTB patients without DM (6 days). In a subgroup analysis, diagnostic delay was associated with smear positivity among PTB patients with DM (OR 3.10, 95%CI 1.66-5.76) and associated with smear positivity (OR 4.38, 95%CI 3.19-6.04), pulmonary cavities (OR 2.62, 95%CI 1.85-3.71) and more symptoms (OR 1.81, 95%CI 1.20-2.73) among PTB patients without DM. CONCLUSIONS DM was associated with longer diagnostic delays, which in turn was associated with more serious clinical presentations of PTB. It is thus necessary to examine risk factors associated with diagnostic delay among PTB patients with and without DM.
Statistical analysis of CCSN/SS7 traffic data from working CCS subnetworks

Reports on an ongoing statistical analysis of actual CCSN traffic data. The data consist of approximately 170 million signaling messages collected from a variety of different working CCS subnetworks. The key findings from the analysis concern: 1) the characteristics of both the telephone call arrival process and the signaling message arrival process; 2) the tail behavior of the call holding time distribution; and 3) the observed performance of the CCSN with respect to a variety of performance and reliability measurements. >
HMDD v2.0: a database for experimentally supported human microRNA and disease associations

The Human microRNA Disease Database (HMDD; available via the Web site at http://cmbi.bjmu.edu.cn/hmdd and http://202.38.126.151/hmdd/tools/hmdd2.html) is a collection of experimentally supported human microRNA (miRNA) and disease associations. Here, we describe the HMDD v2.0 update that presented several novel options for users to facilitate exploration of the data in the database. In the updated database, miRNA–disease association data were annotated in more details. For example, miRNA–disease association data from genetics, epigenetics, circulating miRNAs and miRNA–target interactions were integrated into the database. In addition, HMDD v2.0 presented more data that were generated based on concepts derived from the miRNA–disease association data, including disease spectrum width of miRNAs and miRNA spectrum width of human diseases. Moreover, we provided users a link to download all the data in the HMDD v2.0 and a link to submit novel data into the database. Meanwhile, we also maintained the old version of HMDD. By keeping data sets up-to-date, HMDD should continue to serve as a valuable resource for investigating the roles of miRNAs in human disease.
Attachment affects social information processing: Specific electrophysiological effects of maternal stimuli

Attachment is critical to each individual. It affects the cognitive-affective processing of social information. The present study examines how attachment affects the processing of social information, specifically maternal information. We assessed the behavioral and electrophysiological responses to maternal information (compared to non-specific others) in a Go/No-go Association Task (GNAT) with 22 participants. The results illustrated that attachment affected maternal information processing during three sequential stages of information processing. First, attachment affected visual perception, reflected by enhanced P100 and N170 elicited by maternal information as compared to others information. Second, compared to others, mother obtained more attentional resources, reflected by faster behavioral response to maternal information and larger P200 and P300. Finally, mother was evaluated positively, reflected by shorter P300 latency in a mother + good condition as compared to a mother + bad condition. These findings indicated that the processing of attachment-relevant information is neurologically differentiated from other types of social information from an early stage of perceptual processing to late high-level processing.