Miracle-dz/UniFAR-FTUs huggingface dataset:
The Three-Substituted Indolinone Cyclin-Dependent Kinase 2 Inhibitor 3-[1-(3H-Imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one (SU9516) Kills Human Leukemia Cells via Down-Regulation of Mcl-1 through a Transcriptional Mechanism

Mechanisms of lethality of the three-substituted indolinone and putatively selective cyclin-dependent kinase (CDK)2 inhibitor 3-[1-(3H-imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one (SU9516) were examined in human leukemia cells. Exposure of U937 and other leukemia cells to SU9516 concentrations ≥5 μM rapidly (i.e., within 4 h) induced cytochrome c release, Bax mitochondrial translocation, and apoptosis in association with pronounced down-regulation of the antiapoptotic protein Mcl-1. These effects were associated with inhibition of phosphorylation of the carboxyl-terminal domain (CTD) of RNA polymerase (Pol) II on serine 2 but not serine 5. Reverse transcription-polymerase chain reaction analysis revealed pronounced down-regulation of Mcl-1 mRNA levels in SU9516-treated cells. Similar results were obtained in Jurkat and HL-60 leukemia cells. Furthermore, cotreatment with the proteasome inhibitor N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132) blocked SU9516-mediated Mcl-1 down-regulation, implicating proteasomal degradation in diminished expression of this protein. Ectopic expression of Mcl-1 largely blocked SU9516-induced cytochrome c release, Bax translocation, and apoptosis, whereas knockdown of Mcl-1 by small interfering RNA potentiated SU9516 lethality, confirming the functional contribution of Mcl-1 down-regulation to SU9516-induced cell death. It is noteworthy that SU9516 treatment resulted in a marked increase in reactive oxygen species production, which was diminished, along with cell death, by the free radical scavenger N-acetylcysteine (NAC). We were surprised to find that NAC blocked SU9516-mediated inhibition of RNA Pol II CTD phosphorylation on serine 2, reductions in Mcl-1 mRNA levels, and Mcl-1 down-regulation. Together, these findings suggest that SU9516 kills leukemic cells through inhibition of RNA Pol II CTD phosphorylation in association with oxidative damage and down-regulation of Mcl-1 at the transcriptional level, culminating in mitochondrial injury and cell death.
Determinants of Dengue Virus NS4A Protein Oligomerization

ABSTRACT Flavivirus NS4A protein induces host membrane rearrangement and functions as a replication complex component. The molecular details of how flavivirus NS4A exerts these functions remain elusive. Here, we used dengue virus (DENV) as a model to characterize and demonstrate the biological relevance of flavivirus NS4A oligomerization. DENV type 2 (DENV-2) NS4A protein forms oligomers in infected cells or when expressed alone. Deletion mutagenesis mapped amino acids 50 to 76 (spanning the first transmembrane domain [TMD1]) of NS4A as the major determinant for oligomerization, while the N-terminal 50 residues contribute only slightly to the oligomerization. Nuclear magnetic resonance (NMR) analysis of NS4A amino acids 17 to 80 suggests that residues L31, L52, E53, G66, and G67 could participate in oligomerization. Ala substitution for 15 flavivirus conserved NS4A residues revealed that these amino acids are important for viral replication. Among the 15 mutated NS4A residues, 2 amino acids (E50A and G67A) are located within TMD1. Both E50A and G67A attenuated viral replication, decreased NS4A oligomerization, and reduced NS4A protein stability. In contrast, NS4A oligomerization was not affected by the replication-defective mutations (R12A, P49A, and K80A) located outside TMD1. trans complementation experiments showed that expression of wild-type NS4A alone was not sufficient to rescue the replication-lethal NS4A mutants. However, the presence of DENV-2 replicons could partially restore the replication defect of some lethal NS4A mutants (L26A and K80A), but not others (L60A and E122A), suggesting an unidentified mechanism governing the outcome of complementation in a mutant-dependent manner. Collectively, the results have demonstrated the importance of TMD1-mediated NS4A oligomerization in flavivirus replication. IMPORTANCE We report that DENV NS4A forms oligomers. Such NS4A oligomerization is mediated mainly through amino acids 50 to 76 (spanning the first transmembrane domain [TMD1]). The biological importance of NS4A oligomerization is demonstrated by results showing that mutations of flavivirus conserved residues (E50A and G67A located within TMD1) reduced the oligomerization and stability of the NS4A protein, leading to attenuated viral replication. A systematic mutagenesis analysis demonstrated that flavivirus conserved NS4A residues are important for DENV replication. A successful trans complementation of replication-lethal NS4A mutant virus requires wild-type NS4A in the context of the viral replication complex. The wild-type NS4A protein alone is not sufficient to rescue the replication defect of NS4A mutants. Intriguingly, distinct NS4A mutants yielded different complementation outcomes in the replicon-containing cells. Overall, the study has enhanced our understanding of flavivirus NS4A at the molecular level. The results also suggest that inhibitor blocking of NS4A oligomerization could be explored for antiviral drug discovery.
Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No. 26.

OBJECTIVE To describe the time between treatment for choroidal melanoma and first diagnosis of metastatic disease, sites of metastasis, treatments for metastasis, and time between diagnosis of metastasis and death. DESIGN Prospective, longitudinal follow-up of patients diagnosed with choroidal melanoma who were enrolled in 2 randomized trials conducted by the Collaborative Ocular Melanoma Study Group. METHODS Systemic and laboratory evaluations were performed during follow-up according to a standard protocol for 2320 patients enrolled in the Collaborative Ocular Melanoma Study trials without evidence of melanoma metastasis or other primary cancer at baseline. RESULTS Seven hundred thirty-nine patients were diagnosed with at least 1 site of metastasis during follow-up after treatment for choroidal melanoma. Five- and 10-year cumulative metastasis rates were 25% (95% confidence interval, 23%-27%) and 34% (95% confidence interval, 32%-37%), respectively. Liver was the most common site (89%). The death rate following the report of melanoma metastasis was 80% at 1 year (95% confidence interval, 77%-83%) and 92% at 2 years (95% confidence interval, 89%-94%). Overall survival after metastasis did not vary by baseline size of primary tumor nor treatment for metastasis (when known). Long-term survival after diagnosis of metastasis was uncommon; only 8 patients survived 5 or more years. CONCLUSION Metastasis rate increased significantly with increasing primary tumor dimensions at time of patient enrollment. Prognosis after metastatic disease remains poor. Effective methods are needed to prevent, diagnose, and treat metastasis from choroidal melanoma.
Antihypertensive medication adherence and subsequent healthcare utilization and costs.

OBJECTIVES To evaluate the relationship between adherence to antihypertensive medications (AHMs) and subsequent hospitalizations, emergency department (ED) visits, and costs of care. STUDY DESIGN Retrospective analysis of a national pharmacy benefits database of deidentified pharmacy and medical claims among patients with a diagnosis of hypertension. Adherence was estimated using the medication possession ratio (MPR). METHODS Multivariate logistic and 2-part general linear models were estimated to study the relationship between adherence level (estimated by the MPR) and subsequent association with healthcare costs and cardiovascular (CV)-related hospitalizations and ED visits. RESULTS We identified 625,620 patients with at least 2 claims for AHMs and divided them into 3 cohorts based on year 1 MPR of less than 60% (62,388 patients with low adherence), 60% to 79% (96,226 patients with moderate adherence), and 80% or higher (467,006 patients with high adherence). Patients with high adherence to AHMs were more likely to be older and male, have higher chronic disease scores and lower AHM copayments, and fill a greater percentage of prescriptions by mail order. Year 2 total mean (SD) adjusted healthcare costs were significantly lower for patients with an MPR of 80% or higher ($7182 [$27]) vs 60% to 79% ($7560 [$59]) or less than 60% ($7995 [$73]) (P <.001 for both). In addition, patients with low or moderate adherence had higher age- and sex-adjusted odds of CV-related hospitalizations (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.25-1.41) and ED visits (OR, 1.45; 95% CI, 1.33-1.58) (P <.001 for both). CONCLUSION Adherence to AHMs is associated with significantly lower total healthcare costs and with significantly lower odds of CV-related hospitalizations and ED visits.
Changes of skin perfusion after photodynamic therapy for port wine stain.

OBJECTIVE To obtain an objective assessment of the curative effectiveness of photodynamic therapy (PDT) for port wine stain (PWS), we investigate the relationship between the microvascular perfusion changes of PWS and the blanching of the lesions before and after PDT. METHODS Twenty-four patients (18 females and 6 males with a total of 28 lesions) suffering from PWS were treated with PDT. The lesions of various extents were located on the face and neck. After intravenous injection of photosensitizer hepatoporphyrin derivative (HpD), the copper vapor laser was adopted as light source and the lesions of PWS were irradiated. The laser Doppler perfusion imager (LDI) was used to measure the microcirculatory perfusion of PWS before and after PDT and comparison with the normal skin was done. RESULTS All the lesions showed remarkable decrease of tissue perfusion after PDT. It was shown that the mean, maximal and minimal values of tissue perfusion in the pre-treatment group were significantly higher than those in control group (P < 0.01). Six months after PDT, the mean, maximal and minimal values of perfusion with the lesions were reduced, with significant difference from pre-treatment group (P < 0.01), but no significant difference from control's. The colors of lesions were correlated with decrease of microcirculatory perfusion, which became lightened close to normal skin color without causing any scarring. CONCLUSIONS PDT is one of the most effective modalities for PWS. The microcirculation perfusion can reflect the degrees of PWS objectively. The curative effectiveness of PDT for PWS is due to tissue microcirculation response.
Public Control of the British Bus Industry

The book examines the objectives and economic consequences of the road passenger transport licensing provisions of the Road Traffic Act 1960, the Transport Act 1968, and also the Local Government Act 1972. In this connection attention is also given to the formation of the National Bus Company and the Scottish Transport Group, the work of the passenger transport authorities and executives, and also the co-ordinating functions of the non-metropolitan county councils. Also considered is the question whether the present degree and nature of public control of the bus and coach industry, and the current system of licensing, is in the interests of the consumer, the industry and of the economy generally. The authors discuss the subject in the following chapters: (1) Objectives and legal background; (2) Economic principles; (3) Origins of the 1930 Road Traffic Act; (4) Implementation of the 1980 Act; (5) Some opinions on licensing; (6) A traffic court in action; (7) Costs, revenues and cross subsidy; (8) Conclusions; (9) Summary and proposals. The research work represented by the book was supported by the Rees Jeffreys Road Fund. (TRRL)
Détection de mésusages de médicaments dans les réseaux sociaux (Detection of drug misuse in social media)

Un mésusage apparaît lorsqu’un patient ne respecte pas sa prescription et fait des actions pouvant mener à des effets nocifs. Bien que ces situations soient dangereuses, les patients ne signalent généralement pas les mésusages à leurs médecins. Il est donc nécessaire d’étudier d’autres sources d’information pour découvrir ce qui se passe en réalité. Nous proposons d’étudier les forums de santé en ligne. L’objectif de notre travail consiste à explorer les forums de santé avec des méthodes de classification supervisée afin d’identifier les messages contenant un mésusage de médicament. Notre méthode permet de détecter les mésusages avec une F-mesure allant jusqu’à 0,810. Cette méthode peut aider dans la détection de mésusages et la construction d’un corpus exploitable par les experts pour étudier les types de mésusages commis par les patients.
Low-power circuits design for the Wireless Force Measurement system of the Total Knee Arthroplasty

This paper proposes a novel wireless force measurement system for the Total Knee Arthroplasty (TKA) to improve the ligament balancing procedure during TKA. The force measurement system is comprised of a Wireless Force Measurement Spacer (WFMS) and the display part. They communicate with each other by the Radio Frequency (RF) signal. The WFMS is designed to measure the force between the WFMS and the femoral component of the artificial implants and to transmit the force data wirelessly by a low power transceiver. The display part demonstrates the force data in 3D images in real time. The WFMS composes of a sensors array, a Universal Transducer Interfaces (UTIs) array, a low-power sub-threshold microprocessor and a transceiver. The sub-threshold 8-bit microprocessor is taped out with 0. 18µm CMOS technology. The testing results of the microprocessor show that the leakage power of 46nW and the dynamic power of 385nW@165kHz are achieved with the operating voltage of 350mV. The test results of the system are given and the errors of the system are analyzed. The results verified the reliability of the system. The future work is to design the microprocessor and a lower power transceiver within a single chip.
High HIV Prevalence Among a High-Risk Subgroup of Women Attending Sexually Transmitted Infection Clinics in Pune, India

Objective:To investigate changes over a decade in prevalence and correlates of HIV among high-risk women attending sexually transmitted infection (STI) clinics in Pune, India, who deny a history of commercial sex work (CSW). Design:Cross-sectional. Methods:From 1993 to 2002, 2376 women attending 3 STI clinics in Pune were offered HIV screening. Women who denied CSW were included (n = 1020). Results:Of 1020 women, 21% were HIV infected. The annual HIV prevalence increased from 14% in 1993 to 29% in 2001-2002 (P < 0.001). The change in HIV prevalence over time was paralleled by changes in clinic visitor characteristics; in later periods, women were older, more often employed, less likely to be currently married, and more likely to report condom use. In multivariate analysis, factors independently associated with HIV were calendar period (adjusted odds ratio [AOR], 1.9 for 1997-1999 vs. 1993-1996; 95% CI, 1.2-3.0; AOR, 2.3 for 2000-2002 vs. 1993-1996; 95% CI, 1.5-3.6), lack of formal education (AOR, 2.0; 95% CI, 1.4-2.9), having been widowed (AOR, 3.1; 95% CI, 1.6-6.1), current employment (AOR, 1.8; 95% CI, 1.2-2.6), and genital ulcer disease on examination (AOR, 1.8; 95% CI, 1.2-2.7). Conclusions:Women attending STI clinics in India who deny a history of CSW represent a small, hidden subgroup, likely put at risk for HIV because of high-risk behavior of their male partners, generally their husbands. Educational and awareness efforts that have targeted other subgroups in India (men and CSWs) should also focus on these hard-to-reach women. Risk reduction in this subgroup of Indian women would also be expected to reduce perinatal infections in India.
Auditory temporal coding in dyslexia

Developmental dyslexia is generally believed to result from impaired linguistic processing rather than from deficits in low-level sensory function. Challenging this view, we studied the perception of non-verbal acoustic stimuli and low-level auditory evoked potentials in dyslexic adults. Compared with matched controls, dyslexics were selectively impaired in tasks (frequency discrimination and binaural unmasking) which rely on decoding neural discharges phase-locked to the fine structure of the stimulus. Furthermore, this ability to use phase-locking was related to reading ability. In addition, the evoked potential reflecting phase-locked discharges was significantly smaller in dyslexics. These results demonstrate a low-level auditory impairment in dyslexia traceable to the brainstem nuclei.
Entity oriented action recommendations for actionable knowledge graph generation

Popular search engines have recently utilized the power of knowledge graphs (KGs) to provide specific answers to queries in a direct way. Search engine result pages (SERPs) are expected to provide facts in response to queries that satisfy semantic meaning. This encourages researchers to propose more influential knowledge graph generation techniques. To achieve and advance the technologies related to actionable knowledge graph presentation, creating action recommendations (ARs) is an essential step and a relatively new research direction to nurture research on generating KGs that are optimized for facilitating an entity's actions. An action represents the physical or mental activity of an entity. For example, for the entity "Donald J. Trump", typical potential actions could be "won the US presidential election" or "targets US journalists". In this paper, we describe the generation of relevant action recommendations based on entity instance and entity type. We propose two models that employ different approaches. Our first model exploits semisupervised learning and we introduce entity context vector (ECV) as an entity's distinguishing features for capturing the context of entities to reveal the similarity between entities, grounded on the prominent word2vec model. The second model is a probabilistic approach based on the Naive Bayes Theorem. We extensively evaluate our proposed models. Our first model significantly outperforms probabilistic and supervised learning-based models.
Primate Vocal Communication: A Useful Tool for Understanding Human Speech and Language Evolution?

Abstract Language is a uniquely human trait, and questions of how and why it evolved have been intriguing scientists for years. Nonhuman primates (primates) are our closest living relatives, and their behavior can be used to estimate the capacities of our extinct ancestors. As humans and many primate species rely on vocalizations as their primary mode of communication, the vocal behavior of primates has been an obvious target for studies investigating the evolutionary roots of human speech and language. By studying the similarities and differences between human and primate vocalizations, comparative research has the potential to clarify the evolutionary processes that shaped human speech and language. This review examines some of the seminal and recent studies that contribute to our knowledge regarding the link between primate calls and human language and speech. We focus on three main aspects of primate vocal behavior: functional reference, call combinations, and vocal learning. Studies in these areas indicate that despite important differences, primate vocal communication exhibits some key features characterizing human language. They also indicate, however, that some critical aspects of speech, such as vocal plasticity, are not shared with our primate cousins. We conclude that comparative research on primate vocal behavior is a very promising tool for deepening our understanding of the evolution of human speech and language, but much is still to be done as many aspects of monkey and ape vocalizations remain largely unexplored.
New concepts in the pathogenesis and presentation of Parkinson's disease.

Parkinson's disease (PD) was first described by James Parkinson in 1817. He noted the complex nature of this condition and that non-motor symptoms (NMS) underpinned the classic motor symptoms of PD. The concept of what PD is has therefore undergone substantial changes and it is now recognised that PD is a combined motor and non-motor syndrome and NMS are present during the prodromal phase of PD, starting up to 20 years before the first clinical motor signs emerge. PD may originate from pathology in the gut, olfactory bulb and lower brainstem rather than in the substantia nigra. Complex phenotypes of PD may exist where clinical NMS overshadow motor features. Therapy needs to be adjusted based on motor and non-motor loads, ideally using validated tools. Recently, a multimodal biomarker battery in PD has emerged and might play an important role in the future.
Executive function, more than global cognition, predicts functional decline and mortality in elderly women.

BACKGROUND Functional impairment in community-dwelling older adults is common and is associated with poor outcomes. Our goal was to compare the contribution of impairment in executive function or global cognitive function to predicting functional decline and mortality. METHODS We studied 7717 elderly women enrolled in a prospective study (mean age 73.3 years) and identified women with poor baseline executive function (score > 1 standard deviation [SD] below the mean on the Trail Making Test B (Trails B; n = 957, 12.4%), poor global cognitive function (score > 1 SD below the mean on a modified Mini-Mental State Examination [mMMSE], n = 387, 5.0%), impairment in both (n = 249, 3.2%), or no impairment (n = 6124, 79.4%). We compared level of functional difficulty (Activities of Daily Living [ADLs] and Instrumental ADLs [IADLs]) at baseline and at 6-year follow-up and survival at follow-up. We also determined if the association was independent of age, education, depression, medical comorbidities, and baseline functional ability. RESULTS At baseline, women with Trails B impairment only or impairment on both tests reported the highest proportion of ADL and IADL dependence compared to the other groups. At the 6-year follow-up after adjusting for age, education, medical comorbidities, depression, and baseline ADL or IADL, women with only Trails B impairment were 1.3 times more likely to develop an incident ADL dependence (adjusted odds ratio [OR] = 1.34; 95% confidence interval [CI], 1.07-1.69) and 1.5 times more likely to develop a worsening of ADL dependence (adjusted OR = 1.48; 95% CI, 1.16-1.89) when compared to women with no impairment on either test. In addition, women with only Trails B impairment had a 1.5-fold increased risk of mortality (adjusted hazard ratio [HR] = 1.48; 95% CI, 1.21-1.81). In contrast, women with impairment on only mMMSE were not at increased risk to develop incident ADL or IADL dependence, a worsening of ADL or IADL dependence, or mortality. CONCLUSION Compared to women with no impairment, women with executive function impairment had significantly worse ADL and IADL function cross-sectionally and over 6 years. Individuals with executive dysfunction also had increased risk of mortality. These results suggest that screening of executive function can help to identify women who are at risk for functional decline and decreased survival.