Miracle-dz/UniFAR-FTUs huggingface dataset:
Efficacy and safety of PF299804 versus erlotinib (E): A global, randomized phase II trial in patients (pts) with advanced non-small cell lung cancer (NSCLC) after failure of chemotherapy (CT).

LBA7523 Background: PF299804, a potent, irreversible inhibitor of human epidermal growth factor receptor (HER)-1/EGFR, -2, and -4 tyrosine kinases (TK), is active in E-sensitive and -resistant preclinical models. PF299804 had clinical activity in phase I/II trials in EGFR TK inhibitor (TKI)-refractory NSCLC; a phase III trial is ongoing (BR26). The current trial compared efficacy and safety of PF299804 vs.E in pts with NSCLC after CT failure. METHODS Eligible pts (any histology, ECOG performance status [PS] 0-2, 1/2 CT regimen failures, no prior E, available tumor tissue) were randomized 1:1 to oral PF299804 45 mg or E 150 mg once daily and treated until progression/toxicity. Endpoints included progression-free survival (PFS; primary), overall survival (OS), objective response rate (ORR), safety, and KRAS/EGFR mutation (mu) status. RESULTS 188 pts (median age 60 years, 87% PS 0/1, 41% female, 65% adenocarcinoma (adeno), 25% East Asian, 21% non-smoker, 16% EGFR mu, 16% KRAS mu) were randomized. Baseline characteristics were balanced between arms except for PS 2 ( PF299804 , 20; E, 3 pts). Mu status determination rates were high (KRAS, 81%; EGFR, 77%). Median follow-up was 12 weeks. PF299804 showed significantly longer PFS vs. E in the overall population (p=0.017), with benefit consistent across several subgroups (SG) including EGFR wild type (wt). ORR favored PF299804 (17% vs. 4%; p=0.008). Frequent treatment-related adverse events (TRAEs) for PF299804 vs. E (grade, any/3 or 4): diarrhea (71%/11% v 48%/3%), acne (53%/7% vs. 34%/5%), and rash (26%/4% vs. 37%/2%). Eight pts discontinued due to TRAEs: PF299804 , 6; E, 2 pts. CONCLUSIONS PF299804 showed significant improvement in PFS (primary endpoint) vs. E in all enrolled pts with NSCLC. Common EGFR TKI AEs were more frequent with PF299804. [Table: see text] [Table: see text].
Life History and Color Variants in a Matriline of Oklahoma Salamander (Eurycea tynerensis)

Abstract Until recently, two surface-dwelling species of multi-ribbed brook salamanders (i.e., the metamorphic Eurycea multiplicata griseogaster [Graybelly Salamander], and the strictly paedomorphic E. tynerensis [Oklahoma Salamander]) were recognized as living in the Missouri Ozarks. The current understanding is that a single species (Oklahoma Salamander) is resident in the Ozarks, and that this species is polymorphic for life-history mode from population to population. We recently discovered that multi-ribbed salamanders at two locations in Christian and Barry Counties, MO, show striking polymorphism in eye-coloration, with individuals possessing either gold or black irises. To test whether the gold- and black-eyed forms may be different species, we conducted a phylogeographic analysis of mtDNA variation in multi-ribbed salamanders across the Missouri Ozarks. We present sequence data from the mitochondrial cytochrome-b gene that show that transforming and paedomorphic individuals, and the alternative eye-color morphs can all arise from the same mitochondrially defined matriline, and thus seem to comprise a single species. We hypothesize that color-pattern variation in multi-ribbed salamanders is under simple genetic control.
Motion vector inheritance method for fast HEVC encoding

In this paper, a motion vector inheritance method is proposed in order to reduce motion estimation complexity of the high efficiency video coding (HEVC) encoder. The proposed method refers to the coded-block-flag (CBF) of 2JV × 2JV prediction unit (PU) to see whether or not its sub-partitioned PU can inherit the motion vector of the 2JV × 2JV PU without actual motion estimation. Experimental results show total encoding time reduction of 26.2% and 27.0% under random access condition and low delay condition, respectively, with only 0.5% BDBR loss.
Improvement of Support Vector Clustering using Evolutionary Programming and Bootstrap

Statistical learning theory has three analytical tools which are support vector machine, support vector regression, and support vector clustering for classifica-tion, regression, and clustering respectively. In general, their performances are good because they are constructed by convex optimization. But, there are some problems in the methods. One of the problems is the subjective determination of the parameters for kernel function and regularization by the arts of researchers. Also, the results of the learning machines are depended on the selected parameters. In this paper, we propose an efficient method for objective determina-tion of the parameters of support vector clustering which is the clustering method of statistical learning theory. Using evolutionary algorithm and bootstrap method, we select the parameters of kernel function and regularization constant objectively. To verify improved performances of proposed research, we compare our method with established learning algorithms using the data sets form UCI machine learning repository and synthetic data.
Characterization of companion animal pluripotent stem cells

Pluripotent stem cells have the capacity to grow indefinitely in culture and differentiate into derivatives of the three germ layers. These properties underpin their potential to be used in regenerative medicine. Originally derived from early embryos, pluripotent stem cells can now be derived by reprogramming an adult cell back to a pluripotent state. Companion animals such as horses, dogs, and cats suffer from many injuries and diseases for which regenerative medicine may offer new treatments. As many of the injuries and diseases are similar to conditions in humans the use of companion animals for the experimental and clinical testing of stem cell and regenerative medicine products would provide relevant animal models for the translation of therapies to the human field. In order to fully utilize companion animal pluripotent stem cells robust, standardized methods of characterization must be developed to ensure that safe and effective treatments can be delivered. In this review we discuss the methods that are available for characterizing pluripotent stem cells and the techniques that have been applied in cells from companion animals. We describe characteristics which have been described consistently across reports as well as highlighting discrepant results. Significant steps have been made to define the in vitro culture requirements and drive lineage specific differentiation of pluripotent stem cells in companion animal species. However, additional basic research to compare pluripotent stem cell types and define characteristics of pluripotency in companion animal species is still required. © 2017 International Society for Advancement of Cytometry
Essential role for polymerase specialization in cellular nonhomologous end joining

Significance Nonhomologous end joining (NHEJ) is a DNA double-strand break repair pathway required for development of the adaptive immune response, maintenance of cellular proliferative capacity, and the response to several commonly used cancer treatments. A major challenge faced by this pathway is that chromosome breaks can have dirty end structures, making them difficult to repair. We show here that two mammalian DNA polymerases have an unexpectedly pivotal role in helping resolve such ends. Each is proficient in different contexts and has a differing impact on repair fidelity. This work sheds light on how NHEJ has evolved to be flexible during repair and identifies two polymerases as critical for this process. Nonhomologous end joining (NHEJ) repairs chromosome breaks and must remain effective in the face of extensive diversity in broken end structures. We show here that this flexibility is often reliant on the ability to direct DNA synthesis across strand breaks, and that polymerase (Pol) μ and Pol λ are the only mammalian DNA polymerases that have this activity. By systematically varying substrate in cells, we show each polymerase is uniquely proficient in different contexts. The templating nucleotide is also selected differently, with Pol μ using the unpaired base adjacent to the downstream 5′ phosphate even when there are available template sites further upstream of this position; this makes Pol μ more flexible but also less accurate than Pol λ. Loss of either polymerase alone consequently has clear and distinguishable effects on the fidelity of repair, but end remodeling by cellular nucleases and the remaining polymerase helps mitigate the effects on overall repair efficiency. Accordingly, when cells are deficient in both polymerases there is synergistic impact on NHEJ efficiency, both in terms of repair of defined substrates and cellular resistance to ionizing radiation. Pol μ and Pol λ thus provide distinct solutions to a problem for DNA synthesis that is unique to this pathway and play a key role in conferring on NHEJ the flexibility required for accurate and efficient repair.
Rubrics for assessment item difficulty in engineering courses

A course in Engineering programs is designed and conducted to facilitate students to acquire a set of competencies to meet a subset of Program Outcomes(Graduate Attributes) identified by the accreditation agency. Formative and summative assessments, if in alignment with the competencies, enable the instructor to guide the students to learn well, and to measure the level of attainment of competencies. The difficulty levels of the assessment items are a measure of mastery of the competencies. Well defined difficulty rubrics provide guidelines to the instructor to prepare assessment items with stated difficulty levels. Several difficulty rubrics which are learner dependent or independent, subject specific or non-specific and score-based or score-independent to characterize the difficulty level are reported in the literature. This paper presents a set of learner-independent and score-independent difficulty rubrics. The parameters that characterize these rubrics are arranged in a hierarchy. The nodal parameters are content, task and structure (stimulus) of assessment items. The leaf and atomic parameters are identified in the framework of Anderson-Bloom taxonomy. The parameters for a given assessment item are identified and difficulty is determined by applying weight based and fuzzy logic rule based methods. The efficacy of the proposed item difficulty rubrics is validated by designing different difficulty level items for the course Basics of Digital Systems, and validating the difficulty of the designed items by the subject matter experts.
Genomic Characterization of a South American Phytophthora Hybrid Mandates Reassessment of the Geographic Origins of Phytophthora infestans

As the oomycete pathogen causing potato late blight disease, Phytophthora infestans triggered the famous 19th-century Irish potato famine and remains the leading cause of global commercial potato crop destruction. But the geographic origin of the genotype that caused this devastating initial outbreak remains disputed, as does the New World center of origin of the species itself. Both Mexico and South America have been proposed, generating considerable controversy. Here, we readdress the pathogen’s origins using a genomic data set encompassing 71 globally sourced modern and historical samples of P. infestans and the hybrid species P. andina, a close relative known only from the Andean highlands. Previous studies have suggested that the nuclear DNA lineage behind the initial outbreaks in Europe in 1845 is now extinct. Analysis of P. andina’s phased haplotypes recovered eight haploid genome sequences, four of which represent a previously unknown basal lineage of P. infestans closely related to the famine-era lineage. Our analyses further reveal that clonal lineages of both P. andina and historical P. infestans diverged earlier than modern Mexican lineages, casting doubt on recent claims of a Mexican center of origin. Finally, we use haplotype phasing to demonstrate that basal branches of the clade comprising Mexican samples are occupied by clonal isolates collected from wild Solanum hosts, suggesting that modern Mexican P. infestans diversified on Solanum tuberosum after a host jump from a wild species and that the origins of P. infestans are more complex than was previously thought.
Future Directions for Research on Early Intervention for Young Children at Risk for Social Anxiety

Anxiety disorders are common among young children, with earlier onset typically associated with greater severity and persistence. A stable behaviorally inhibited (BI) temperament and subsequent shyness and social withdrawal (SW) place children at increased risk of developing anxiety disorders, particularly social anxiety. In this Future Directions article, we briefly review developmental and clinical research and theory that point to parenting and peer interactions as key moderators of both the stability of BI/SW and risk for later anxiety, and we describe existing interventions that address early BI/SW and/or anxiety disorders in young children. We recommend that future research on early intervention to disrupt the trajectory of anxiety in children at risk (a) be informed by both developmental science and clinical research, (b) incorporate multiple levels of analysis (including both individual and contextual factors), (c) examine mediators that move us closer to understanding how and why treatments work, (d) be developed with the end goal of dissemination, (e) examine moderators of outcome toward the goal of treatment efficiency, (f) consider transdiagnostic or modular approaches, (g) integrate technology, and (h) consider cultural norms regarding BI/SW/anxiety and parenting.
Inventory control policies for random lead times

Updates to classical two-level inventory control policies are discussed for inventory control systems (ICS) with random lead times. The conventional zero time ICS-model problem is stated. The solution lies in the two criteria generalization of the conventional inventory control problem. Formulas are derived for calculating corrections to the classical inventory control problem variables. Simulation results are presented.
Combined MR lymphangiography and MR imaging-guided needle localization of sentinel lymph nodes using Gadomer-17.

OBJECTIVE The goals of our study were to determine the technical feasibility of dynamic MR lymphangiography for detecting sentinel lymph nodes using Gadomer-17 contrast material to compare these results to the clinically standardized blue dye contrast agent, and to show MR imaging-guided needle localization marking of the sentinel nodes. MATERIALS AND METHODS Six anesthetized swine underwent MR imaging before and for 1 hr after interstitial injection of Gadomer-17 in the posterior tongue and intradermally in the stifle (knee). Using MR imaging guidance, we percutaneously placed a histology needle into the sentinel node or nodes. A standardized intraoperative sentinel node detection procedure was then performed using isosulfan blue contrast agent. Sentinel nodes identified on the MR images were compared with and matched to those identified by biopsy needle localization and the isosulfan blue contrast agent. RESULTS. Interstitial and intradermal injection of Gadomer-17 resulted in a lasting, increased MR signal in the regional lymph nodes. Seven sentinel nodes were identified in both the neck and the groin, with one pig showing two sentinel nodes in the neck and another showing two sentinel nodes in the groin. In all cases, the isosulfan blue contrast agent agreed with the location of the sentinel node determined by Gadomer-17 and marked with the needle. CONCLUSION In this large animal model, dynamic MR angiography of sentinel lymph nodes is technically feasible using a contrast agent (Gadomer-17) and can be easily combined with MR imaging-guided needle localization.
TouchString: a flexible linear multi-touch sensor for prototyping a freeform multi-touch surface

We propose the concept of prototyping a multi-touch surface of an arbitrary form using a flexible linear multi-touch sensor that we call TouchString. We defined the conceptual structure of a TouchString, and implemented an example prototype of a TouchString. We verified the feasibility of the concept by demonstrating a few basic application scenarios using the prototype.
The use of U‐500 regular insulin in the management of patients with obesity and insulin resistance

The rise in prevalence of obesity and diabetes has created a challenge in managing increasing numbers of patients who require high doses of insulin. This article reviews the published literature on the properties of U‐500 insulin and its use in clinical practice. U‐500 insulin is likely to have a longer time to peak effect and a longer duration of action than similar doses of U‐100 insulin. Evidence for its use in clinical practice rests on retrospective case series, which suggests that the use of U‐500 insulin either by multiple daily injections or a continuous subcutaneous insulin infusion is effective in improving glycaemic control. To prevent insulin dosing and administration errors, great care must be taken in providing staff and patient education, and in developing policies for the management of patients on U‐500 insulin who are admitted to hospital.
Discussion of The Economic Consequences of Increased Disclosure

The basis for the study by Leuz and Verrecchia (hereafter LV) is the link between information asymmetries, market liquidity, and the cost of capital. The theory states that information asymmetries among market participants reduce expected liquidity in the market for a firm's shares through the introduction of adverse selection. The reduction in liquidity raises transaction costs and ultimately the cost of capital. Previous empirical research that has studied the correlation between disclosure levels and the information asymmetry component of the cost of capital has produced mixed results, perhaps because measuring both (changes in) disclosure levels and the information asymmetry component of the cost of capital of firms is very difficult. LV observe that an additional explanation for the mixed results might be that the power of the tests in the previous studies is weakened because they focus on the U.S. capital market, which is characterized both by high liquidity and by a high level of disclosure. As a consequence, commitments to additional disclosure in this context could lead to relatively small benefits that may not be measured accurately. LV present an innovative extension of the current empirical disclosure literature by focusing on the German capital market setting. German accounting standards and
Sequential decision-making: Theory and evidence for irrigator water allocation trade participation and volumetric choices

Greater understanding of irrigator water trade decision-making processes provides insight into the efficient reallocation of water resources between competing uses. Water trade decisions are often modelled as single processes, although results in this paper suggest that sequential decision modelling is more appropriate. We devised a theoretical model of experienced and naive irrigators based on the search literature, and observed sequential decision-making in water allocation trade decisions using sample-selection techniques. There is evidence of positive selection effects, which motivate different drivers for the decision to participate in water trade and the subsequent decision about how much water to buy or sell.
H-ras, K-ras, and inner plasma membrane raft proteins operate in nanoclusters with differential dependence on the actin cytoskeleton

Plasma membrane compartmentalization imposes lateral segregation on membrane proteins that is important for regulating signal transduction. We use computational modeling of immunogold spatial point patterns on intact plasma membrane sheets to test different models of inner plasma membrane organization. We find compartmentalization at the nanoscale level but show that a classical raft model of preexisting stable domains into which lipid raft proteins partition is incompatible with the spatial point patterns generated by the immunogold labeling of a palmitoylated raft marker protein. Rather, ≈30% of the raft protein exists in cholesterol-dependent nanoclusters, with ≈70% distributed as monomers. The cluster/monomer ratio (number of proteins in clusters/number of proteins outside clusters) is independent of expression level. H-rasG12V and K-rasG12V proteins also operate in nanoclusters with fixed cluster/monomer ratios that are independent of expression level. Detailed calibration of the immunogold imaging protocol suggests that radii of raft and RasG12V protein nanoclusters may be as small as 11 and 6 nm, respectively, and shows that the nanoclusters contain small numbers (6.0-7.7) of proteins. Raft nanoclusters do not form if the actin cytoskeleton is disassembled. The formation of K-rasG12V but not H-rasG12V nanoclusters also is actin-dependent. K-rasG12V but not H-rasG12V signaling is abrogated by actin cytoskeleton disassembly, which shows that nanoclustering is critical for Ras function. These findings argue against stable preexisting domains on the inner plasma membrane in favor of dynamic actively regulated nanoclusters similar to those proposed for the outer plasma membrane. RasG12V nanoclusters may facilitate the assembly of essential signal transduction complexes.
Dopamine regulates melanopsin mRNA expression in intrinsically photosensitive retinal ganglion cells

In mammals a subpopulation of retinal ganglion cells are intrinsically photosensitive (ipRGCs), express the photopigment melanopsin, and play an important role in the regulation of the nonimage‐forming visual system. We have recently reported that melanopsin mRNA and protein levels in the rat retina are under photic and circadian control. The aim of the present work was to investigate the mechanisms that control melanopsin expression in the rat retina. We discovered that dopamine (DA) is involved in the regulation of melanopsin mRNA, possibly via dopamine D2 receptors that are located on these ipRGCs. Interestingly, we also discovered that pituitary adenylate cyclase‐activating peptide (PACAP) mRNA levels are affected by DA. Dopamine synthesis and release in the retina are regulated by the rod and the cone photoreceptors via retinal circuitry; our new data indicate that DA controls melanopsin expression, indicating that classical photoreceptors may modulate the transcription of this new photopigment. Our study also suggests that DA may have an important role in mediating the light signals that are used for circadian entrainment and for other responses that are mediated by the nonimage‐forming visual system.
A chromatin localization screen reveals poly (ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage

Many proteins that respond to DNA damage are recruited to DNA lesions. We used a proteomics approach that coupled isotopic labeling with chromatin fractionation and mass spectrometry to uncover proteins that associate with damaged DNA, many of which are involved in DNA repair or nucleolar function. We show that polycomb group members are recruited by poly(ADP ribose) polymerase (PARP) to DNA lesions following UV laser microirradiation. Loss of polycomb components results in IR sensitivity of mammalian cells and Caenorhabditis elegans. PARP also recruits two components of the repressive nucleosome remodeling and deacetylase (NuRD) complex, chromodomain helicase DNA-binding protein 4 (CHD4) and metastasis associated 1 (MTA1), to DNA lesions. PARP plays a role in removing nascent RNA and elongating RNA polymerase II from sites of DNA damage. We propose that PARP sets up a transient repressive chromatin structure at sites of DNA damage to block transcription and facilitate DNA repair.