Miracle-dz/UniFAR-FTUs huggingface dataset:
Repression of Prespliceosome Complex Formation at Two Distinct Steps by Fox-1/Fox-2 Proteins

ABSTRACT Precise and robust regulation of alternative splicing provides cells with an essential means of gene expression control. However, the mechanisms that ensure the tight control of tissue-specific alternative splicing are not well understood. It has been demonstrated that robust regulation often results from the contributions of multiple factors to one particular splicing pathway. We report here a novel strategy used by a single splicing regulator that blocks the formation of two distinct prespliceosome complexes to achieve efficient regulation. Fox-1/Fox-2 proteins, potent regulators of alternative splicing in the heart, skeletal muscle, and brain, repress calcitonin-specific splicing of the calcitonin/CGRP pre-mRNA. Using biochemical analysis, we found that Fox-1/Fox-2 proteins block prespliceosome complex formation at two distinct steps through binding to two functionally important UGCAUG elements. First, Fox-1/Fox-2 proteins bind to the intronic site to inhibit SF1-dependent E′ complex formation. Second, these proteins bind to the exonic site to block the transition of E′ complex that escaped the control of the intronic site to E complex. These studies provide evidence for the first example of regulated E′ complex formation. The two-step repression of presplicing complexes by a single regulator provides a powerful and accurate regulatory strategy.
Falls and cognitive decline in Mexican Americans 75 years and older

Background Little is known about long-term emotional and cognitive consequences of falls. We examined the association between falls and subsequent cognitive decline, and tested the hypothesis that depression would mediate any falls–cognition association among cognitively intact Hispanic Elders. Methods We used data from the Hispanic Established Population for the Epidemiological Study of the Elderly to examine change in Mini Mental State Examination (MMSE) scores over the 6-year period according to number of falls. All participants (N=1,119) had MMSE scores ≥21 and complete data on Center for Epidemiologic Studies of Depression Scale, social and demographic factors, medical conditions (diabetes, heart attack, stroke, and hypertension), and hand grip muscle strength. Results At baseline, participants’ mean age was 80.8 years (range, 74–109), mean education was 6.3 years (range, 0–17), and mean MMSE was 25.2 (range, 21–30). Of the 1,119 participants, 15.8% experienced one fall and 14.4% had two or more falls. In mixed model analyses, having two or more falls was associated with greater decline in MMSE score (estimate =−0.81, standard error =0.19, P<0.0001) compared to having no fall, after adjusting for age, sex, marital status, and education. The magnitude of the association decreased (estimate =−0.65, standard error =0.19, P=0.0007) when adjustment was made for high depressive symptoms, suggesting a possible mediating effect of depression on the falls–cognition association. Female sex, high level of education, and high performance in hand grip muscle strength were associated with a slower decline in MMSE scores. Conclusion Having two or more falls was independently associated with steeper decline in cognition over 6 years, with a possible mediating effect of depression on the falls–cognition association.
Therapeutic Immunization with Human Immunodeficiency Virus Type 1 (HIV-1) Peptide-Loaded Dendritic Cells Is Safe and Induces Immunogenicity in HIV-1-Infected Individuals

ABSTRACT Treatments for human immunodeficiency virus type 1 (HIV-1)-positive individuals that augment HIV-1 suppression and have potential for achieving long-term control of HIV-1 viremia in the absence of antiretroviral therapy (ART) are urgently needed. We therefore conducted a phase I, clinical safety trial of a dendritic cell (DC)-based vaccination strategy as immunotherapy for HIV-1-positive individuals on ART. We studied 18 HIV-1-positive subjects on ART who underwent leukapheresis to obtain peripheral blood mononuclear cells for DC generation from monocytes cultured with cytokines. Mature DC were pulsed with three HIV-1 HLA*A0201 Gag, Env, and Pol peptides and one influenza A virus matrix protein peptide. The vaccine was administered to donors randomized to receive two vaccinations, either intravenously or subcutaneously. The primary end points were safety and tolerability of two doses of peptide-DC vaccine (3 million versus 10 million). Secondary end points included gamma interferon (IFN-γ) enzyme-linked immunospot assay responses and clinical correlates of an immune response to vaccination. Autologous DC-peptide vaccine was safe, well tolerated, and feasible for use in all participants. Adverse events were rare. Although the trial was not powered to assess an immunologic response, a significantly increased frequency of HIV-1 peptide-specific IFN-γ-positive cells was observed 2 weeks following the second vaccine, with three individuals responding to all four peptides. DC vaccination was safe, was feasible, and showed promise of immunogenicity in ART-treated, HIV-1-positive individuals. Additional studies of DC immunization strategies for HIV-1 infection are warranted.
The DRD2 gene 957C>T polymorphism is associated with Posttraumatic Stress Disorder in war veterans

Background: Variations in genes related to the dopaminergic pathway have been implicated in neuropsychiatric disorders such as schizophrenia, substance misuse, Alzheimer's disease and Post Traumatic Stress Disorder (PTSD). A single nucleotide polymorphism (SNP) (957C>T) and a deletion polymorphism (‐141delC) in the DRD2 gene and a SNP (Taq1A) in a gene directly downstream of DRD2 have all been implicated in dopamine functioning in the brain. Methods: To test the importance of these three polymorphisms in PTSD susceptibility, a genetic screen was performed in 127 war veterans diagnosed with PTSD and 228 control individuals without a history of PTSD. Results: No significant association was found between PTSD and the Taq1A or ‐141delC polymorphisms. However, a significant association was observed with PTSD and the 957C>T polymorphism. PTSD individuals were more likely to carry the C allele compared to the controls (P=0.021). Conclusions: Our findings suggest that the 957C>T polymorphism in the DRD2 gene is one of the genetic factors for susceptibility to PTSD. Depression Anxiety, 2009. © 2008 Wiley‐Liss, Inc.
Simple and Efficient Multiple Kernel Learning by Group Lasso

We consider the problem of how to improve the efficiency of Multiple Kernel Learning (MKL). In literature, MKL is often solved by an alternating approach: (1) the minimization of the kernel weights is solved by complicated techniques, such as Semi-infinite Linear Programming, Gradient Descent, or Level method; (2) the maximization of SVM dual variables can be solved by standard SVM solvers. However, the minimization step in these methods is usually dependent on its solving techniques or commercial softwares, which therefore limits the efficiency and applicability. In this paper, we formulate a closed-form solution for optimizing the kernel weights based on the equivalence between group-lasso and MKL. Although this equivalence is not our invention, our derived variant equivalence not only leads to an efficient algorithm for MKL, but also generalizes to the case for Lp-MKL (p ≥ 1 and denoting the Lp-norm of kernel weights). Therefore, our proposed algorithm provides a unified solution for the entire family of Lp-MKL models. Experiments on multiple data sets show the promising performance of the proposed technique compared with other competitive methods.
Approximate reasoning for real-time probabilistic processes

We develop a pseudo-metric analogue of bisimulation for generalized semiMarkov processes. The kernel of this pseudo-metric corresponds to bisimulation; thus we have extended bisimulation for continuous-time probabilistic processes to a much broader class of distributions than exponential distributions. This pseudo-metric gives a useful handle on approximate reasoning in the presence of numerical information - such as probabilities and time - in the model. We give a fixed point characterization of the pseudo-metric. This makes available coinductive reasoning principles for reasoning about distances. We demonstrate that our approach is insensitive to potentially ad hoc articulations of distance by showing that it is intrinsic to an underlying uniformity. We provide a logical characterization of this uniformity using a real-valued modal logic. We show that several quantitative properties of interest are continuous with respect to the pseudo-metric. Thus, if two processes are metrically close, then observable quantitative properties of interest are indeed close.
Inverse relationship between physical activity and arterial stiffness in adults with hypertension.

BACKGROUND Physical activity has beneficial effects on arterial stiffness among healthy adults. There is a lack of data on this relationship in adults with hypertension. The majority of studies which have examined physical activity and arterial stiffness have used subjective measures of activity. The aim of this study was to investigate the relationship between objectively measured habitual physical activity and arterial stiffness in individuals with newly diagnosed essential hypertension. METHODS Adults attending an outpatient hypertension clinic were recruited into this cross sectional study. Physical activity was measured using a triaxial accelerometer. Pulse wave velocity (PWV) and augmentation index (AIx) were measured using applanation tonometry. Participant's full lipid profile and glucose were determined through the collection of a fasting blood sample. RESULTS Fifty-three adults [51(14) years, 26 male] participated, 16 of whom had the metabolic syndrome. Inactivity was positively correlated with PWV (r = .53, P < .001) and AIx (r = .48, P < .001). There were significant inverse associations between habitual physical activity of all intensities and both AIx and PWV. In stepwise regression, after adjusting for potential confounders, physical activity was a significant predictor of AIx and PWV. CONCLUSION Habitual physical activity of all intensities is associated with reduced arterial stiffness among adults with hypertension.
miR-125b Promotes Early Germ Layer Specification through Lin28/let-7d and Preferential Differentiation of Mesoderm in Human Embryonic Stem Cells

Unlike other essential organs, the heart does not undergo tissue repair following injury. Human embryonic stem cells (hESCs) grow indefinitely in culture while maintaining the ability to differentiate into many tissues of the body. As such, they provide a unique opportunity to explore the mechanisms that control human tissue development, as well as treat diseases characterized by tissue loss, including heart failure. MicroRNAs are small, non-coding RNAs that are known to play critical roles in the regulation of gene expression. We profiled the expression of microRNAs during hESC differentiation into myocardial precursors and cardiomyocytes (CMs), and determined clusters of human microRNAs that are specifically regulated during this process. We determined that miR-125b overexpression results in upregulation of the early cardiac transcription factors, GATA4 and Nkx2-5, and accelerated progression of hESC-derived myocardial precursors to an embryonic CM phenotype. We used an in silico approach to identify Lin28 as a target of miR-125b, and validated this interaction using miR-125b knockdown. Anti-miR-125b inhibitor experiments also showed that miR-125b controls the expression of miRNA let-7d, likely through the negative regulatory effects of Lin28 on let-7. We then determined that miR-125b overexpression inhibits the expression of Nanog and Oct4 and promotes the onset of Brachyury expression, suggesting that miR-125b controls the early events of human CM differentiation by inhibiting hESC pluripotency and promoting mesodermal differentiation. These studies identified miR-125b as an important regulator of hESC differentiation in general, and the development of hESC-derived mesoderm and cardiac muscle in particular. Manipulation of miR-125b-mediated pathways may provide a novel approach to directing the differentiation of hESC-derived CMs for cell therapy applications.
TESTQUAL: Conceptualizing Software Testing as a Service

Software testing has emerged as a distinct and critical component in software development. This paper argues that software testing should be conceptualized as a concurrent service throughout the software development process rather than being viewed as a sequential line of responsibility. Testing as a service has two key aspects: (1) a service to developers, and (2) a service to end users. This paper draws from the service quality and SERVQUAL literature to propose a structured measurement tool for testing as a service. Software quality is the most prominent outcome for TESTQUAL. The potential antecedents and outcomes of TESTQUAL are briefly discussed. The implications to research and practice of TESTQUAL are also discussed.
Brain Meets Brawn: Why Grid and Agents Need Each Other

The Grid and agent communities both develop concepts and mechanisms for open distributed systems, albeit from different perspectives. The Grid community has historically focused on "brawn": infrastructure, tools, and applications for reliable and secure resource sharing within dynamic and geographically distributed virtual organizations. In contrast, the agents community has focused on "brain": autonomous problem solvers that can act flexibly in uncertain and dynamic environments. Yet as the scale and ambition of both Grid and agent deployments increase, we see a convergence of interests, with agent systems requiring robust infrastructure and Grid systems requiring autonomous, flexible behaviors. Motivated by this convergence of interests, we review the current state of the art in both areas, review the challenges that concern the two communities, and propose research and technology development activities that can allow for mutually supportive efforts.
A Trust Establishment Scheme for Cluster-Based Sensor Networks

Because sensor networks(WSN) often deployed in a wicked and hostile environment, individual nodes of WSN could be easily compromised by the adversary. Once a node's cryptographic key is compromised, an attacker may completely impersonate it and introduce arbitrary false information into the network. Basic cryptographic mechanisms are often not effective in this situation. In this paper we developed the trust and reputation management scheme to secure network in cluster-based Sensor Networks. In the cluster, the surveillance node(SN) use watchdog mechanism to monitor the behavior of every cluster node(CN), maintain reputation for other nodes and use it to evaluate their trustworthiness. The cluster head(CH) finally computed the trust value, decide node revocation and select SN newly.
Analysis of co-assembly and co-localization of ameloblastin and amelogenin

Epithelially-derived ameloblasts secrete extracellular matrix proteins including amelogenin, enamelin, and ameloblastin. Complex intermolecular interactions among these proteins are believed to be important in controlling enamel formation. Here we provide in vitro and in vivo evidence of co-assembly and co-localization of ameloblastin with amelogenin using both biophysical and immunohistochemical methods. We performed co-localization studies using immunofluorescence confocal microscopy with paraffin-embedded tissue sections from mandibular molars of mice at 1, 5, and 8 days of age. Commercially-available ameloblastin antibody (M300) against mouse ameloblastin residues 107–407 and an antibody against full-length recombinant mouse (rM179) amelogenin were used. Ameloblastin-M300 clearly reacted along the secretory face of ameloblasts from days 1–8. Quantitative co-localization was analyzed (QCA) in several configurations by choosing appropriate regions of interest (ROIs). Analysis of ROIs along the secretory face of ameloblasts revealed that at day 1, very high percentages of both the ameloblastin and amelogenin co-localized. At day 8 along the ameloblast cells the percentage of co-localization remained high for the ameloblastin whereas co-localization percentage was reduced for amelogenin. Analysis of the entire thickness on day 8 revealed no significant co-localization of amelogenin and ameloblastin. With the progress of amelogenesis and ameloblastin degradation, there was a segregation of ameloblastin and co-localization with the C-terminal region decreased. CD spectra indicated that structural changes in ameloblastin occurred upon addition of amelogenin. Our data suggest that amelogenin-ameloblastin complexes may be the functional entities at the early stage of enamel mineralization.
JAK2 V617F Genotype Is a Strong Determinant of Blast Transformation in Primary Myelofibrosis

Purpose The influence of JAK2 V617F mutation on blast transformation (BT) and overall survival (OS) in primary myelofibrosis (PMF) is controversial. In a large cohort of patients we applied competing risks analysis for studying the influence of JAK2V617F mutation on BT in PMF. Patients and Methods In 462 PMF–fibrotic type patients (bone marrow [BM] fibrosis grade >0) we computed the incidence of BT and death in the framework of Cox regression analysis and of Fine and Gray competing risks analysis for BT. Results At the Cox regression analysis, having either a wild-type (wt) or a homozygous JAK2V617F genotype were factors for BT (HR, 1.98 and 2.04, respectively, with respect to the heterozygous genotype), but not for OS. At the competing risks regression analysis, the risk for BT in wt and homozygous V617F patients increased with respect to Cox analysis, giving a sHR of 2.17 and 2.12, respectively. Correcting the results for the variables that could have influence on BT, JAK2V617F wt and homozygous genotypes remained independently associated with BT. In a validation cohort of 133 independent cases with PMF-prefibrotic type (BM fibrosis grade = 0), the BT predictive model including JAK2V617F genotype and older age retained high discriminant capacity (C statistics, 0.70; 95% CI, 0.47 to 0.92). Conclusion The accumulation of mutated alleles in the JAK2V617F clone or the selective acquisition of a proliferative advantage in the wt clone are two relevant routes to BT in PMF. The influence of these results on treatment decisions with anti-JAK2 agents should be tested.
Comparison of selected thermal indices in the northwest of Iran

The present study compared simple thermal indices and the indices derived from energy budget models in the northwest of Iran. For this purpose, the air temperature, solar radiation, relative humidity, cloud, cover and wind speed of 13 meteorological stations in the northwest of Iran during the the period of 1986 to 2007 were selected for comparison. The results which were extracted using Bioklima and RayMan models, showed that the indices based on human energy balance had a significant correlation with each other (with R2 above 90%), and the lowest R2 (70%) was related to Subjective temperature index (STI). The indices based on relatively simple formulas had low correlation with Universal Thermal Climate Index (UTCI) and Physiologically Equivalent Temperature (PET). The probable reason for this lack of conformity was the lack of radiation factor in the equations. Furthermore, UTCI was very sensitive to the changes in air temperature, solar radiation, relative humidity and wind speed, especially. In this regard, it represented the response of the human body. The findings of this analysis indicated that UTCI and PET indices were the most suitable indices which could be used in determining thermal comfort conditions.
On Group Averaging for SO(n,1)

The technique known as group averaging provides powerful machinery for the study of constrained systems. However, it is likely to be well-defined only in a limited set of cases. Here, we investigate the possibility of using a "renormalized" group averaging in certain models. The results of our study may indicate a general connection between superselection sectors and the rate of divergence of the group averaging integral.
Controlled Clinical Trial of a Self-Help for Anxiety Intervention for Patients Waiting for Psychological Therapy

Abstract This study was a controlled clinical trial in which patients were offered a brief low cost, low intensity self-help intervention while waiting for psychological therapy. A CBT based self-help pack was given to patients with significant anxiety problems and no attempt was made to exclude patients on the basis of severity or co-morbidity. The treatment group received the intervention immediately following assessment and the control group after a delay of 8 weeks so comparisons between the two groups were made over 8 weeks. Although there was some support for the effectiveness of the self help intervention, with a significant time x group interaction for CORE-OM scores, this was not significant with the intention to treat analysis, nor for HADS anxiety and depression scores and the effect size was low. A follow up evaluation suggested some patients attributed significant goal attainment to the intervention. The findings suggest the routine use of self-help interventions in psychological therapies services should be considered although further more adequately powered research is required to identify the type of patients and problems that most benefit, possible adverse effects and the effect on subsequent uptake of and engagement in therapy.
The use of elderly living donors in renal transplantation

The safety and the results of using living donors above the age of 60 years were studied. In 235 consecutive donors the complications were not different in elderly (n=70) compared to younger donors. Graft survival and function were studied in 232 consecutive 1-HLA-haplotype mismatched grafts. Graft survival at 1 year was equivalent (87% vs. 92%), but after 2–6 years graft survival was inferior in recipients of older grafts (n=62). The recipients of older grafts were 10 years older, and patient death with functioning graft was a more frequent cause of graft loss. Up to 4 years serum creatinine levels were significantly higher, but stable, in recipients of older grafts; at 5 years the difference was not significant. It is concluded that the use of elderly living donors is safe. Taking recipient age into consideration, graft survival is not different in the two groups. Graft function in older grafts is some what inferior, but stable.
Monomer arrangement in HSP90 dimer as determined by decoration with N and C-terminal region specific antibodies.

Electron microscopy using the low-angle rotary shadowing replica method showed that the HSP90 dimer consists of four globular domains aligning in a tandem fashion. When decorated with two monoclonal antibodies against epitopes mapped on the N-terminal region of HSP90, these antibodies bound to both ends of the HSP90 dimer. A C-terminal region specific antibody was shown to bind to the side of HSP90. These results support a model for HSP90 dimer whereby two HSP90 monomers are arranged in an antiparallel fashion and dimerize through the C-terminal domain. Treatment of HSP90 at elevated temperatures or with ATP at room temperature, though not with ADP, induces molecular transformation of the linear HSP90 dimer into an O-ring-shaped structure.