Miracle-dz/UniFAR-FTUs huggingface dataset:
Recessive Loss-of-Function Mutation in the Pacemaker HCN2 Channel Causing Increased Neuronal Excitability in a Patient with Idiopathic Generalized Epilepsy

The hyperpolarization-activated Ih current, coded for by hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, controls synaptic integration and intrinsic excitability in many brain areas. Because of their role in pacemaker function, defective HCN channels are natural candidates for contributing to epileptogenesis. Indeed, Ih is pathologically altered after experimentally induced seizures, and several independent data indicate a link between dysfunctional HCN channels and different forms of epilepsy. However, direct evidence for functional changes of defective HCN channels correlating with the disease in human patients is still elusive. By screening families with epilepsy for mutations in Hcn1 and Hcn2 genes, we found a recessive loss-of-function point mutation in the gene coding for the HCN2 channel in a patient with sporadic idiopathic generalized epilepsy. Of 17 screened members of the same family, the proband was the only one affected and homozygous for the mutation. The mutation (E515K) is located in the C-linker, a region known to affect channel gating. Functional analysis revealed that homomeric mutant, but not heteromeric wild-type/mutant channels, have a strongly inhibited function caused by a large negative shift of activation range and slowed activation kinetics, effectively abolishing the HCN2 contribution to activity. After transfection into acutely isolated newborn rat cortical neurons, homomeric mutant, but not heteromeric wild type/mutant channels, lowered the threshold of action potential firing and strongly increased cell excitability and firing frequency when compared with wild-type channels. This is the first evidence in humans for a single-point, homozygous loss-of-function mutation in HCN2 potentially associated with generalized epilepsy with recessive inheritance.
The MEME Suite

The MEME Suite is a powerful, integrated set of web-based tools for studying sequence motifs in proteins, DNA and RNA. Such motifs encode many biological functions, and their detection and characterization is important in the study of molecular interactions in the cell, including the regulation of gene expression. Since the previous description of the MEME Suite in the 2009 Nucleic Acids Research Web Server Issue, we have added six new tools. Here we describe the capabilities of all the tools within the suite, give advice on their best use and provide several case studies to illustrate how to combine the results of various MEME Suite tools for successful motif-based analyses. The MEME Suite is freely available for academic use at http://meme-suite.org, and source code is also available for download and local installation.
Attention Reshapes Center-Surround Receptive Field Structure in Macaque Cortical Area MT

Directing spatial attention to a location inside the classical receptive field (cRF) of a neuron in macaque medial temporal area (MT) shifts the center of the cRF toward the attended location. Here we investigate the influence of spatial attention on the profile of the inhibitory surround present in many MT neurons. Two monkeys attended to the fixation point or to 1 of 2 random dot patterns (RDPs) placed inside or next to the cRF, whereas a third RDP (the probe) was briefly presented in quick succession across the cRF and surround. The probe presentation responses were used to compute a map of the excitatory receptive field and its inhibitory surround. Attention systematically reshapes the receptive field profile, independently shifting both center and surround toward the attended location. Furthermore, cRF size is changed as a function of relative distance to the attentional focus: attention inside the cRF shrinks it, whereas directing attention next to the cRF expands it. In addition, we find systematic changes in surround inhibition and cRF amplitude. This nonmultiplicative push–pull modulation of the receptive field's center-surround structure optimizes processing at and near the attentional focus to strengthen the representation of the attended stimulus while reducing influences from distractors.
Telomerase inhibition and cell growth arrest by G-quadruplex interactive agent in multiple myeloma.

OBJECTIVE The aim of this study was to test the efficacy of telomerase inhibitor (TMPyP4 [tetra(N-methyl-4-pyridyl)-porphyrin chloride]; a G-quadruplex-intercalating porphyrin) as a potential therapeutic agent for multiple myeloma. MATERIALS AND METHODS We studied telomere length, telomerase activity, and effect of telomerase inhibition in multiple myeloma cells. Several myeloma cell lines were analyzed for telomerase activity, telomere length, and gene expression. Three myeloma cell lines (U266, ARH77, and ARD) were treated with TMPyP4 for 3-4 weeks. Viable cell number was assessed by trypan blue exclusion, and nature of cell death was determined by annexin labeling and/or DNA fragmentation. In situ oligo ligation technique was used to identify specific DNase I-type DNA cleavage. RESULTS We report high telomerase activity and shortened telomeres in myeloma cells compared to normal B cells. We have also observed inhibition of telomerase activity, reduction in telomere length, and decline of myeloma cell growth, as measured by trypan blue dye exclusion, following exposure to TMPyP4. Exposure to porphyrin reduced telomerase activity of U266, ARH77, and ARD myeloma cells by 98%, 92%, and 99%, respectively. Exposure to porphyrin had no effect on viability for the first 14 days, followed by death of 75-90% of cells over the next 2 weeks. The nature of cell death was apoptotic, as determined by annexin and DNA nick labeling. Majority of cells showed DNA fragmentation specific to caspase-3-activated DNase I. CONCLUSIONS These results demonstrate anti-proliferative activity of G-quadruplex-intercalating agents, and suggest telomerase as an important therapeutic target for myeloma therapy.
Pancreatic Lipase Immunoreactivity in Serum of Dogs with Diabetic Ketoacidosis

Background Diabetic ketoacidosis (DKA) is a relatively common endocrine disorder in dogs and is routinely associated with concurrent pancreatic injury. Objectives The aims of this study were to determine the prevalence of pancreatic injury in dogs with DKA based on measurement of pancreatic lipase immunoreactivity in serum (PLI); compare demographic, clinicopathologic, and ultrasonographic findings in dogs with and without evidence of concurrent pancreatic injury; determine the impact of pancreatic injury on duration of hospitalization and short‐term outcome. Animals One hundred and nineteen dogs with DKA with or without concurrent pancreatic injury. Methods Retrospective study. Dogs with DKA were divided into three groups on the basis of PLI results: positive for pancreatic injury (PLI pos), negative for pancreatic injury (PLI neg), and not tested (PLI na). Demographics, clinicopathologic test results, findings on abdominal ultrasonography (AUS), duration of hospitalization, and short‐term outcome were compared between the three groups. Results Based on serum PLI activity, 45 dogs (73%) with DKA had evidence of concurrent pancreatic injury. Median total carbon dioxide was significantly lower in the PLI pos dogs compared to the PLI neg dogs. There was fair agreement (κ = 0.26) between serum PLI activity and AUS. Evidence of pancreatic injury was not associated with significantly longer periods of hospitalization (PLI pos median 6 days, range 4–7 days, PLI neg median 4 days, range 3–6 days) and did not influence short‐term outcome (PLI pos failure to survive to discharge 11/45, 24%, PLI neg failure to survive to discharge 2/17, 12%). Clinical Importance Concurrent pancreatic injury is common in dogs with DKA, but did not affect prognosis in this population of dogs.
Racial and Political Dynamics of an Approaching “Majority-Minority” United States

Do demographic shifts in the racial composition of the United States promote positive changes in the nation’s racial dynamics? Change in response to the nation’s growing diversity is likely, but its direction and scope are less clear. This review integrates emerging social-scientific research that examines how Americans are responding to the projected changes in the racial/ethnic demographics of the United States. Specifically, we review recent empirical research that examines how exposure to information that the United States is becoming a “majority-minority” nation affects racial attitudes and several political outcomes (e.g., ideology, policy preferences), and the psychological mechanisms that give rise to those attitudes. We focus primarily on the reactions of members of the current dominant racial group (i.e., white Americans). We then consider important implications of these findings and propose essential questions for future research.
Factors Influencing Participation Rate in a Baseline Survey of a Genetic Cohort in Japan

Background Although many studies have examined factors that influence the response to postal questionnaires, few have addressed baseline recruitment for cohort studies involving genetic analyses. The aim of this study was to describe the method used for a baseline survey, the Japan Multi-institutional Collaborative Cohort Study (J-MICC Study), in Saga Prefecture, and to examine the factors that might influence the recruitment of participants in such studies. Methods The Saga J-MICC Study is an ongoing population-based prospective cohort study of the genetic and environmental interactions associated with lifestyle-related disease. From 2005 through 2007, a total of 61 447 residents between the ages of 40 and 69 were invited by mail to participate in this study. The survey date and time were arranged by telephone. Results Among that population, 31 002 (50.5%) responded and 12 078 (19.7%) agreed to participate. A completed questionnaire and blood pressure and anthropometric data were collected from all participants; blood, DNA specimens, and accelerometer measures were obtained from the great majority of them. Female sex and older age were associated with a higher participation rate. In addition, the convenience of the survey location and the sending of a reminder significantly improved the participation rate (odds ratio, 1.3). Conclusions Our findings suggest that making the survey location as convenient as possible and sending a reminder can both substantially improve participation rate in population-based studies.
A Method for the Simultaneous Estimation of Selection Intensities in Overlapping Genes

Inferring the intensity of positive selection in protein-coding genes is important since it is used to shed light on the process of adaptation. Recently, it has been reported that overlapping genes, which are ubiquitous in all domains of life, seem to exhibit inordinate degrees of positive selection. Here, we present a new method for the simultaneous estimation of selection intensities in overlapping genes. We show that the appearance of positive selection is caused by assuming that selection operates independently on each gene in an overlapping pair, thereby ignoring the unique evolutionary constraints on overlapping coding regions. Our method uses an exact evolutionary model, thereby voiding the need for approximation or intensive computation. We test the method by simulating the evolution of overlapping genes of different types as well as under diverse evolutionary scenarios. Our results indicate that the independent estimation approach leads to the false appearance of positive selection even though the gene is in reality subject to negative selection. Finally, we use our method to estimate selection in two influenza A genes for which positive selection was previously inferred. We find no evidence for positive selection in both cases.
Atypical Pathogens as Etiologic Agents in Hospitalized Patient with Community-Acquired Pneumonia in Korea: A Prospective Multi-Center Study

Local epidemiologic data on the etiologies of patients hospitalized with community-acquired pneumonia (CAP) is needed to develop guidelines for clinical practice. This study was conducted prospectively to determine the proportion of atypical bacterial pathogens in adults patients hospitalized with CAP in Korea between October 2001 and December 2002. Microbiological diagnosis was determined by serology for antibodies to Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. Nucleic acid of M. pneumoniae and C. pneumoniae in respiratory samples and Legionella antigen in urine samples were detected. The study population consisted of 126 patients (71 males, 55 females), averaging 54.6 yr (SD±17.8), whose paired sera were available. An etiologic diagnosis for atypical pathogens was made in 18 patients (14.3%): C. pneumoniae 9 (7.1%), M. pneumoniae 8 (6.3%), and L. pneumophila 3 patients (2.4%). Streptococcus preumoniae and other typical pathogens were isolated from 36 patients (28.6%). Of 126 patients, 16 (12.7%) were admitted to intensive care unit and atypical pathogens were identified in 5 patients (31.3%). Initial clinical features of patients with pneumonia due to atypical, typical or undetermined pathogens were indistinguishable. We conclude that atypical pathogens should be seriously considered in hospitalized patients with CAP, when initiating empiric treatment in Korea.
Fatherhood in Brazil, Bangladesh, Russia, Japan, and Australia

This article illustrates that the roles of fathers are highly variable and context-dependent. Research data from five diverse societies (Brazil, Bangladesh, Russia, Japan, and Australia) show that fathers, fathering, and fatherhood differ within societies according to eight types of contextual influence. Examples are provided of each contextual factor: (1) geographical location (e.g., dispersion of fathers across huge land masses in Russia and Australia; impact of dense populations in Japan and Bangladesh); (2) long-term historical legacies (centuries of patriarchy in Brazil) and short-term historical events (fall of communism in Russia); (3) family characteristics (joint, extended families of Bangladesh; small Japanese families); (4) economic factors (high standards of living in Australia and Japan); (5) work-related conditions (long work hours in Australia; level of encouragement for paternal work leave); (6) societal norms and values (social expectations for Russian fathers to be disengaged and uninvolved); (7) ethnic groupings (homogeneity of Japanese; impact of Islam on Bengali fathers); and (8) patterns of immigration and emigration (emigration from Bangladesh; immigration to Brazil).
Object-oriented Analysis Using Natural Language Processing

There is often a wealth of extant domain-specific, natural-language data available to help guide developers of object-oriented systems. This data is generally amenable to natural language processing in order to derive valuable design information. However, from a review of the field, we contend that current approaches have not been able to extract all the semantic and design detail that is present in such data. For instance: we see a lack of dynamic system representations; we detect reluctance for researchers to adopt hybrid solutions where users confirm and elaborate automated analyses; and we suggest there is work needed to determine a comprehensive repertoire of potential relationships between system components. In partial pursuit of such a manifesto, this paper mentions briefly our algorithmic proposal for processing natural language into UML with supplemental user involvement.
Advanced DInSAR Based on Coherent Pixels: Development and Results Using CPT Technique

RESUME This paper presents the activities undertaken and the results obtained in the project “Development of algorithms for the exploitation of ERS – ENVISAT using the Coherent Pixels Technique”. The project objective was to develop an advanced interferometric technique based on the coherence stability and study the applicability in a group of joint interferograms obtained from both ERS and ENVISAT images. The Coherent Pixels Technique (CPT) algorithm is capable of extracting the linear and non-linear movement of a given scenery, as well as the DEM error and atmospheric artefacts. Useful information can be obtained with a small stack of interferograms compared with other advanced DInSAR techniques. A Graphical User Interface has been developed in order to provide a friendly handling of data. Two main scenarios have been used: Paris and Madrid to show the capabilities of the CPT algorithm and the Graphical User Interface. The deformation results obtained during validation tests will be presented, proving that CPT algorithm is a good tool for extracting terrain deformation with a reduced number of images.
Tracing worked examples: effects on learning in geometry

Abstract Previous research has verified the benefits obtained when learners trace out worked examples with the index finger. Our study conducted two experiments to explore the reasons for this phenomenon and its generalizability. Experiment 1 compared the learning effects among tracing, non-tracing, and cueing methods. The cueing method was included to isolate the variable of drawing attention. Students employing the tracing method obtained higher transfer test scores compared to those employing the cueing and non-tracing methods, rating the far transfer test as easier. The tracing effect was verified to have a greater impact on learning than solely focusing learners’ attention. Experiment 2 compared the learning effects among three methods – tracing with the index finger, tracing with a computer mouse, and observing others tracing. Students who merely observed tracing obtained lower far transfer scores than those who traced either with their finger or with the mouse, rating the tests as more difficult. There was no significant difference between the other two groups. Tracing promotes learning more than merely observing tracing. The learning benefits of tracing partly stem from the fact that it is action-based and can be generalized to mouse tracing.
College Students’ Attitudes and Behaviors Related to Sun Safety and Appearance in Relation to Health Information-Seeking Behavior and Social Media Use: Cross-Sectional Study

Background: Skin cancer is the most common type of cancer in the United States. Rates of melanoma, a malignant form of skin cancer, are on the rise and are high among people under 30 years of age. Objective: This study aims to explore factors related to sun protection and tanning behavior and examine the influence of social media use and health information-seeking behaviors (HISB) on sun protection actions among a group of college students. Methods: In this cross-sectional study, students (N=258) at a large public university completed a survey that included questions on sun safety and tanning attitudes and behaviors, as well as HISB. A sun protection behavior score was created on the basis of behaviors related to seeking shade, using sunscreen, tanning booth and bed use, and the number of lifetime blistering sunburns. Multivariate logistic regression analyses were performed to assess associations between high and low sun protection behavior and sun safety and tanning attitudes and HISB. Results: The majority of participants were females (164/258, 63.8%), 31.0% (80/258) were white, and the mean age was 20.3 (SD 4.1) years. Females (odds ratio [OR] 0.42, 95% CI 0.22-0.81) and believers that suntan improves appearance (OR 0.25, 95% CI 0.10-0.66) were less likely to have “high” sun protection behaviors. Conclusions: The cultural belief that having a suntan improves appearance, especially among female college students, results in low sun protection behaviors. Interventions can be developed to improve skin cancer-related HISB among college students with the aim of developing better cognizance of skin cancer and sun protection behaviors.
How to Discount Cashflows with Time-Varying Expected Returns

While many studies document that the market risk premium is predictable and that betas are not constant, the dividend discount model ignores time-varying risk premiums and betas. We develop a model to consistently value cashflows with changing risk-free rates, predictable risk premiums and conditional betas in the context of a conditional CAPM. Practical valuation is accomplished with an analytic term structure of discount rates, with different discount rates applied to expected cashflows at different horizons. Using constant discount rates can produce large mis-valuations, which, in portfolio data, are mostly driven at short horizons by market risk premiums and at long horizons by time-variation in risk-free rates and factor loadings.
Optimal Trust Network Analysis with Subjective Logic

Trust network analysis with subjective logic (TNA-SL) simplifies complex trust graphs into series-parallel graphs by removing the most uncertain paths to obtain a canonical graph. This simplification could in theory cause loss of information and thereby lead to sub-optimal results. This paper describes a new method for trust network analysis which is considered optimal because it does not require trust graph simplification, but instead uses edge splitting to obtain a canonical graph. The new method is compared with TNA-SL, and our simulation shows that both methods produce equal results. This indicates that TNA-SL in fact also represents an optimal method for trust network analysis and that the trust graph simplification does not affect the result.
SPANStore: cost-effective geo-replicated storage spanning multiple cloud services

By offering storage services in several geographically distributed data centers, cloud computing platforms enable applications to offer low latency access to user data. However, application developers are left to deal with the complexities associated with choosing the storage services at which any object is replicated and maintaining consistency across these replicas. In this paper, we present SPANStore, a key-value store that exports a unified view of storage services in geographically distributed data centers. To minimize an application provider's cost, we combine three key principles. First, SPANStore spans multiple cloud providers to increase the geographical density of data centers and to minimize cost by exploiting pricing discrepancies across providers. Second, by estimating application workload at the right granularity, SPANStore judiciously trades off greater geo-distributed replication necessary to satisfy latency goals with the higher storage and data propagation costs this entails in order to satisfy fault tolerance and consistency requirements. Finally, SPANStore minimizes the use of compute resources to implement tasks such as two-phase locking and data propagation, which are necessary to offer a global view of the storage services that it builds upon. Our evaluation of SPANStore shows that it can lower costs by over 10x in several scenarios, in comparison with alternative solutions that either use a single storage provider or replicate every object to every data center from which it is accessed.
Inquilinus limosus in Patients with Cystic Fibrosis, Germany

We identified Inquilinus limosus, a recently described α-proteobacterium, in sputum of 2 patients with cystic fibrosis whose respiratory tracts were persistently colonized for >9 months. We present data on the epidemiology, antimicrobial susceptibility, and molecular characteristics of I. limosus.