Miracle-dz/UniFAR-FTUs huggingface dataset:
Optimal Experimental Design for Parameter Estimation of a Cell Signaling Model

Differential equation models that describe the dynamic changes of biochemical signaling states are important tools to understand cellular behavior. An essential task in building such representations is to infer the affinities, rate constants, and other parameters of a model from actual measurement data. However, intuitive measurement protocols often fail to generate data that restrict the range of possible parameter values. Here we utilized a numerical method to iteratively design optimal live-cell fluorescence microscopy experiments in order to reveal pharmacological and kinetic parameters of a phosphatidylinositol 3,4,5-trisphosphate (PIP3) second messenger signaling process that is deregulated in many tumors. The experimental approach included the activation of endogenous phosphoinositide 3-kinase (PI3K) by chemically induced recruitment of a regulatory peptide, reversible inhibition of PI3K using a kinase inhibitor, and monitoring of the PI3K-mediated production of PIP3 lipids using the pleckstrin homology (PH) domain of Akt. We found that an intuitively planned and established experimental protocol did not yield data from which relevant parameters could be inferred. Starting from a set of poorly defined model parameters derived from the intuitively planned experiment, we calculated concentration-time profiles for both the inducing and the inhibitory compound that would minimize the predicted uncertainty of parameter estimates. Two cycles of optimization and experimentation were sufficient to narrowly confine the model parameters, with the mean variance of estimates dropping more than sixty-fold. Thus, optimal experimental design proved to be a powerful strategy to minimize the number of experiments needed to infer biological parameters from a cell signaling assay.
Scalable proximity estimation and link prediction in online social networks

Proximity measures quantify the closeness or similarity between nodes in a social network and form the basis of a range of applications in social sciences, business, information technology, computer networks, and cyber security. It is challenging to estimate proximity measures in online social networks due to their massive scale (with millions of users) and dynamic nature (with hundreds of thousands of new nodes and millions of edges added daily). To address this challenge, we develop two novel methods to efficiently and accurately approximate a large family of proximity measures. We also propose a novel incremental update algorithm to enable near real-time proximity estimation in highly dynamic social networks. Evaluation based on a large amount of real data collected in five popular online social networks shows that our methods are accurate and can easily scale to networks with millions of nodes. To demonstrate the practical values of our techniques, we consider a significant application of proximity estimation: link prediction, i.e., predicting which new edges will be added in the near future based on past snapshots of a social network. Our results reveal that (i) the effectiveness of different proximity measures for link prediction varies significantly across different online social networks and depends heavily on the fraction of edges contributed by the highest degree nodes, and (ii) combining multiple proximity measures consistently yields the best link prediction accuracy.
Complex reference values for endocrine and special chemistry biomarkers across pediatric, adult, and geriatric ages: establishment of robust pediatric and adult reference intervals on the basis of the Canadian Health Measures Survey.

BACKGROUND Defining laboratory biomarker reference values in a healthy population and understanding the fluctuations in biomarker concentrations throughout life and between sexes are critical to clinical interpretation of laboratory test results in different disease states. The Canadian Health Measures Survey (CHMS) has collected blood samples and health information from the Canadian household population. In collaboration with the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER), the data have been analyzed to determine reference value distributions and reference intervals for several endocrine and special chemistry biomarkers in pediatric, adult, and geriatric age groups. METHODS CHMS collected data and blood samples from thousands of community participants aged 3 to 79 years. We used serum samples to measure 13 immunoassay-based special chemistry and endocrine markers. We assessed reference value distributions and, after excluding outliers, calculated age- and sex-specific reference intervals, along with corresponding 90% CIs, according to CLSI C28-A3 guidelines. RESULTS We observed fluctuations in biomarker reference values across the pediatric, adult, and geriatric age range, with stratification required on the basis of age for all analytes. Additional sex partitions were required for apolipoprotein AI, homocysteine, ferritin, and high sensitivity C-reactive protein. CONCLUSIONS The unique collaboration between CALIPER and CHMS has enabled, for the first time, a detailed examination of the changes in various immunochemical markers that occur in healthy individuals of different ages. The robust age- and sex-specific reference intervals established in this study provide insight into the complex biological changes that take place throughout development and aging and will contribute to improved clinical test interpretation.
Sociodemographic and lifestyle characteristics are associated with antioxidant intake and the consumption of their dietary sources during pregnancy

Abstract Objective To analyse the associations of selected sociodemographic and lifestyle factors with the intake of antioxidant nutrients and consumption of their main dietary sources among pregnant women. Design A population-based cohort study. Dietary intake during pregnancy was assessed by a self-administered FFQ one to three months after the delivery. Setting Type 1 Diabetes Prediction and Prevention (DIPP) Project. Subjects Subjects comprised 3730 women (70·1 % of those invited) who entered the DIPP Nutrition Study after delivering a child at increased genetic risk for type 1 diabetes at the university hospitals in Oulu and Tampere, Finland, 1997–2002. Results All sociodemographic and lifestyle factors studied showed significant associations with antioxidant intake in multiple regression models adjusting for all other factors. Older and more educated women tended to have higher intake of most antioxidants. Parity was positively associated with retinol intake and inversely with vitamin C intake. Smokers had lower intakes of most antioxidants. Only the partner’s education was positively associated with high intake of fruits, whereas own education was positively associated with berry consumption. Vegetable consumption was positively associated with partner’s education except for women with academic education, who tended to have high vegetable consumption irrespective of partner’s education. Conclusions Young women, smokers and those with a low education are at risk for low antioxidant intake and non-optimal food choices during pregnancy.
Comparison Between the Cassia Fistula`s Emulsion With Polyethylene Glycol (PEG4000) in the Pediatric Functional Constipation: A Randomized Clinical Trial

Background There are few effective drugs for pediatric functional constipation (FC). Objectives Comparing the effectiveness of Cassia fistula’s emulsion (CFE) with Polyethylene glycol (PEG4000) in FC; and evaluation of safety of both drugs in the treatment of FC. Materials and Methods A randomized open label, prospective, controlled, parallel-group clinical trial was carried on 109 children (M/F: 63/46; mean age ± SD: 59.7 ± 28.8 months) in Amirkola children’s hospital, Babol, Iran. The inclusion criteria were based on diagnosis of FC according to the Rome III criteria and age range between 2 - 15 years. They received CFE or PEG randomly for 4 weeks. Frequencies of defecation, severity of pain, consistency of stool, fecal incontinence and retentive posturing were compared between the two groups and with baselines. Children were counted as improved when they exited from Rome III criteria of FC. Results Fifty seven patients were assigned to receive PEG and 52 patients received CFE. After 4weeks of medication, 86.5% of children in CFE group and 77.1% in PEG group (RR = 1.121, CI95%:0.939 - 1.338) exited from the criteria of FC. All measurable criteria improved in both groups without any significant difference, except in the frequency of defecation that in CFE group (10.96 ± 5.7) was significantly more than PEG group (6.9 ± 3.5) (P < 0.0001). Compliances of PEG were significantly better in the 2 first weeks (P = 0.002, 0.008) but not in third and fourth week (P = 0.061, 0.062). None of these two drugs cause clinically significant side effects. Conclusions CFE can be as effective as PEG in the 4-weeks treatment of children with FC.
Structure and Diversity of Tree Species at the College of Forestry and Fisheries, University of Agriculture Makurdi, Benue State, Nigeria

Tree composition and distribution is very helpful in understanding the status of forest stands, regeneration, and diversity for conservation purposes. The structure of forest estates largely depends on the ecological characteristics of sites, species diversity and regeneration status of tree species. Quantitative information on composition, distribution, or abundance of trees species is of key importance to understanding the status (composition and structure) of a forest estate; also for decision-making, planning and implementation of conservation strategy of the forest estate(s).
A Giant Planet Around a Metal-Poor Star of Extragalactic Origin

Unlikely Planet Most known extrasolar planets orbit stars similar to the Sun. Very few planets have been detected around metal-poor stars whose abundances of elements other than hydrogen and helium are much lower than those of the Sun, or around stars that are at a late stage in their evolution. Setiawan et al. (p. 1642, published online 18 November) report the detection of a close-in giant planet around a metal-poor star belonging to a group of stars that formed in a satellite galaxy of the Milky Way. The star has gone past the red giant phase of stellar evolution, when stars like the Sun expand up to many times their original size, and so it is unclear why the planet was not engulfed by the star as it expanded. A planet is observed to orbit a star whose properties are different from those of all other known planet-hosting stars. Stars in their late stage of evolution, such as horizontal branch stars, are still largely unexplored for planets. We detected a planetary companion around HIP 13044, a very metal-poor star on the red horizontal branch, on the basis of radial velocity observations with a high-resolution spectrograph at the 2.2-meter Max-Planck Gesellschaft–European Southern Observatory telescope. The star’s periodic radial velocity variation of P = 16.2 days caused by the planet can be distinguished from the periods of the stellar activity indicators. The minimum mass of the planet is 1.25 times the mass of Jupiter and its orbital semimajor axis is 0.116 astronomical units. Because HIP 13044 belongs to a group of stars that have been accreted from a disrupted satellite galaxy of the Milky Way, the planet most likely has an extragalactic origin.
Examining trait mindfulness, emotion dysregulation, and quality of life in multiple sclerosis.

OBJECTIVE Dispositional mindfulness exhibits a positive association with quality of life (QoL). One potential mechanism for this association is enhanced emotion regulation abilities. Individuals with multiple sclerosis (MS) experience a range of physical, cognitive, and affective impairments, thus reducing overall QoL. The current cross-sectional study examines the relation between trait mindfulness and QoL, mediated by emotion dysregulation in individuals with MS. METHOD Ninety-five participants with self-reported MS completed an online survey that incorporated self-report measures of trait mindfulness, emotion dysregulation, and QoL. Although clinically significant depression was exclusionary, we observed a wide range of depressive symptoms in our sample. These scores were thus entered as a moderator in the mediation analysis. RESULTS Dispositional mindfulness correlated positively with QoL, with lower emotion dysregulation partially mediating the correlation. Depression scores moderated the observed mediation, such that the effect was stronger in those with higher symptoms of depression. CONCLUSIONS Trait mindfulness is positively associated with QoL in individuals with MS. Reduced emotion dysregulation may be a critical pathway linking mindfulness and QoL in MS, especially in those with higher symptoms of depression.
Relationship between patient reported experience (PREMs) and patient reported outcomes (PROMs) in elective surgery

Objective Our aim was to see if the reporting of better experiences by elective surgical patients was associated with better outcomes (effectiveness and safety). The objectives were to: describe the distribution of experience scores and any association with patients’ characteristics; determine the relationship of experience with effectiveness and with safety; and explore the influence of patient characteristics, year and provider on the relationship between experience and effectiveness. Methods Patients undergoing one of three procedures from 2010 to 2012 in England who completed a patient reported outcome measure (PROM) questionnaire before and after surgery and a patient reported experience measure (PREM) questionnaire. Data on 4089 hip replacement patients, 4501 knee replacements and 1793 groin hernia repairs. Regression analysis was used to examine associations between disease-specific and generic PROMs and PREMs. Results There was a weak positive association between experience and effectiveness for all three procedures (correlation coefficient with disease-specific PROMs for hip and knee replacements 0.2 and with EQ-5D 0.1 for all three procedures). The aspect of experience most strongly associated with a better outcome was the level of communication with and trust in their doctor. A higher experience score of 1 SD (about 1.5 on a 10-point scale) was associated with about 30% less likelihood of the patient reporting a complication. There was no difference between the eight dimensions of experience. All the relationships observed were consistent over time, between different types of patients (age, sex, socioeconomic status) and between providers. Conclusions Patients distinguish between the three domains of quality when reporting their experience and outcome. If the weak positive associations between domains were shown to be causal, there would be implications for maximising performance measures for providers.
Impact of Diffusion-Weighted Imaging Lesion Volume on the Success of Endovascular Reperfusion Therapy

Background and Purpose— Diffusion-weighted imaging (DWI) lesion volume is associated with poor outcome after thrombolysis, and it is unclear whether endovascular therapies are beneficial for large DWI lesion. Our aim was to assess the impact of pretreatment DWI lesion volume on outcomes after endovascular therapy, with a special emphasis on patients with complete recanalization. Methods— We analyzed data collected between April 2007 and November 2011 in a prospective clinical registry. All acute ischemic stroke patients with complete occlusion of internal carotid artery or middle cerebral artery treated by endovascular therapy were included. DWI lesion volumes were measured by the RAPID software. Favorable outcome was defined by modified Rankin Scale of 0 to 2 at 90 days. Results— A total of 139 acute ischemic stroke patients were included. Median DWI lesion volume was 14 cc (interquartile range, 5–43) after a median onset time to imaging of 110 minutes (interquartile range, 77–178). Higher volume was associated with less favorable outcome (adjusted odds ratio, 0.55; 95% confidence interval, 0.31–0.96). A complete recanalization was achieved in 65 (47%) patients after a median onset time of 238 minutes (interquartile range, 206–285). After adjustment for volume, complete recanalization was associated with more favorable outcome (adjusted odds ratio, 6.32; 95% confidence interval, 2.90–13.78). After stratification of volume by tertiles, complete recanalization was similarly associated with favorable outcome in the upper 2 tertiles (P<0.005). Conclusions— Our results emphasize the importance of initial DWI volume and recanalization on clinical outcome after endovascular treatment. Large DWI lesions may still benefit from recanalization in selected patients.
The role of monsoon low‐level jet in modulating heavy rainfall events

Monsoon low‐level jet (MLLJ) is an important component of Asian summer monsoon circulation, which is responsible for large‐scale distribution and variability of rainfall over the Indian subcontinent. The evolution of MLLJ characteristics prior to heavy rainfall days and its changes which lead to instances of heavy rainfall over the south‐western coast of India are studied. The European Centre for Medium Range Weather Forecasts (ECMWF) re‐analysis data and India Meteorological Department (IMD) rainfall data during 1979–2007 were used for this study. It is found that the MLLJ core speed, westerly wind depth, zonal water vapour flux, horizontal wind shear and cyclonic vorticity show a steady increase towards the day of heavy rainfall and gradually decrease thereafter. The intensification of these parameters not only brings in abundant moisture but also triggers convection, thereby resulting in the formation of heavy rainfall during monsoon season. The large‐scale advection of moisture brought about by strengthening of MLLJ is shown to be a prerequisite for heavy rainfall over the Indian subcontinent. An interesting result of this study is that heavy rainfall days may have some predictability by continuous monitoring of the progression of MLLJ.
Microenvironment and Immunology Immune Inhibitory Molecules Lag-3 and Pd-1 Synergistically Regulate T-cell Function to Promote Tumoral Immune Escape

Inhibitory receptors on immune cells are pivotal regulators of immune escape in cancer. Among these inhibitory receptors, CTLA-4 (targeted clinically by ipilimumab) serves as a dominant off-switch while other receptors such as PD-1 and LAG-3 seem to serve more subtle rheostat functions. However, the extent of synergy and cooperative interactions between inhibitory pathways in cancer remain largely unexplored. Here, we reveal extensive coexpression of PD-1 and LAG-3 on tumor-infiltrating CD4 þ and CD8 þ T cells in three distinct transplantable tumors. Dual anti–LAG-3/anti–PD-1 antibody treatment cured most mice of established tumors that were largely resistant to single antibody treatment. Despite minimal immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, dual knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in multiple organs, leading to eventual lethality. However, Lag3 À/À Pdcd1 À/À mice showed markedly increased survival from and clearance of multiple transplantable tumors. Together, these results define a strong synergy between the PD-1 and LAG-3 inhibitory pathways in tolerance to both self and tumor antigens. In addition, they argue strongly that dual blockade of these molecules represents a promising combinatorial strategy for cancer.
A caching model of operating system kernel functionality

Operating system research has endeavored to develop micro-kernels that provide modularity, reliability and security improvements over conventional monolithic kernels. However, the resulting kernels have been slower, larger and more error-prone than desired. These efforts have also failed to provide sufficient application control of resource management required by sophisticated applications. This paper describes a caching model of operating system functionality as implemented in the Cache Kernel, the supervisor-mode component of the V++ operating system. The Cache Kernel caches operating system objects such as threads and address spaces just as conventional hardware caches memory data. User-mode application kernels handle the loading and writeback of these objects, implementing application-specific management policies and mechanisms. Experience with implementing the Cache Kernel and measurements of its performance on a multiprocessor suggest that the caching model can provide competitive performance with conventional monolithic operating systems, yet provides application-level control of system resources, better modularity, better scalability, smaller size and a basis for fault containment.
Early Lymph Vessel Development From Embryonic Stem Cells

Objective—The purpose of this study was to establish a model system for lymph vessel development based on directed differentiation of murine embryonic stem cells. Methods and Results—Stem cells were aggregated to form embryoid bodies, and subsequently cultured in 3-dimensional collagen matrix for up to 18 days. Treatment with vascular endothelial growth factor (VEGF)-C and VEGF-A individually enhanced formation of lymphatic vessel structures, although combined treatment with VEGF-C and VEGF-A was most potent and gave rise to a network of LYVE-1, podoplanin, Prox1, and VEGF receptor-3 positive lymphatic vessel structures running parallel to and apparently emanating from, capillaries. In contrast, fibroblast growth factor-2, hepatocyte growth factor, or hypoxia had little or no effect on the development of the early lymphatics. Further, cells of hematopoietic origin were shown to express lymphatic markers. In summary, different subpopulations of lymphatic endothelial cells were identified on the basis of differential expression of several lymphatic and blood vessel markers, indicating vascular heterogeneity. Conclusions—We conclude that the present model closely mimics the early steps of lymph vessel development in mouse embryos.
A New Admittance-Type Haptic Interface for Bimanual Manipulations

The concept of a new mobile haptic interface for bimanual manipulations in 6 DOFs is presented. The design of this mobile haptic interface is based on a modular system consisting of two components: two admittance-type haptic interfaces and a mobile platform. While the haptic interfaces cover only parts of the human arm workspace, the mobile platform extends these to arbitrarily wide remote environments. This paper mainly addresses the design and control concepts of the haptic interfaces, which are planned to be mounted on the mobile platform. The interfaces dispose of a large workspace and a high force/torque capability. A special design and control concept of the haptic interfaces makes it possible to decouple translational from rotational movements. This decoupling helps to significantly simplify the control algorithms that handle the interaction between the single components. Evaluation results concerning the Cartesian position tracking performance and the impedance display fidelity are provided. In addition, the following performance measures are analyzed: dextrous workspace, output capability, and backdrivability. In order to reduce the measurement effort, some of these measures are determined by model-based, others by measurement-based performance evaluation.