Miracle-dz/UniFAR-FTUs huggingface dataset:
Emergence of Protease Inhibitor Resistance–Associated Mutations in Plasma HIV-1 Precedes That in Proviruses of Peripheral Blood Mononuclear Cells by More Than a Year

HIV-1 genotype assay using plasma viruses has been widely applied for detection of resistant viruses in infected individuals, whereas there are only a few reports about proviral genotype in peripheral blood mononuclear cells (PBMCs). To determine which sample, plasma or PBMC, should be used for early detection of drug-resistant viruses during antiretroviral treatment, we analyzed 275 plasma-derived and 211 PBMC-derived HIV-1 protease sequences obtained from HIV-1–infected patients during protease inhibitor (PI) therapy. In 70 of 107 pairs (65.4%) of plasma and PBMC samples taken from the same blood draws, the numbers of PI resistance–associated mutations in the plasma-derived genotype were different from those in the PBMC-derived genotype. Plasma viruses had more PI resistance–associated mutations than PBMC proviruses (P = 0.0004). Analysis of serial samples showed that plasma-derived genotype assay could detect primary mutations about 425 days earlier than PBMC-derived genotype when the plasma viral load was less than 104 copies/mL. Our data suggest that genetic turnover of PBMC proviruses is slower than that of plasma viruses and that time lag between emergence of mutations in plasma-derived and PBMC-derived genotypes correlates inversely with viral load. Plasma viruses should be the material of choice for early detection of drug resistance during antiretroviral treatment.
An End-to-End Neural Network for Polyphonic Music Transcription

We present a neural network model for polyphonic music transcription. The architecture of the proposed model is analogous to speech recognition systems and comprises an acoustic model and a music language mode}. The acoustic model is a neural network used for estimating the probabilities of pitches in a frame of audio. The language model is a recurrent neural network that models the correlations between pitch combinations over time. The proposed model is general and can be used to transcribe polyphonic music without imposing any constraints on the polyphony or the number or type of instruments. The acoustic and language model predictions are combined using a probabilistic graphical model. Inference over the output variables is performed using the beam search algorithm. We investigate various neural network architectures for the acoustic models and compare their performance to two popular state-of-the-art acoustic models. We also present an efficient variant of beam search that improves performance and reduces run-times by an order of magnitude, making the model suitable for real-time applications. We evaluate the model's performance on the MAPS dataset and show that the proposed model outperforms state-of-the-art transcription systems.
Gaussian Mixture Modeling by Exploiting the Mahalanobis Distance

In this paper, the expectation-maximization (EM) algorithm for Gaussian mixture modeling is improved via three statistical tests. The first test is a multivariate normality criterion based on the Mahalanobis distance of a sample measurement vector from a certain Gaussian component center. The first test is used in order to derive a decision whether to split a component into another two or not. The second test is a central tendency criterion based on the observation that multivariate kurtosis becomes large if the component to be split is a mixture of two or more underlying Gaussian sources with common centers. If the common center hypothesis is true, the component is split into two new components and their centers are initialized by the center of the (old) component candidate for splitting. Otherwise, the splitting is accomplished by a discriminant derived by the third test. This test is based on marginal cumulative distribution functions. Experimental results are presented against seven other EM variants both on artificially generated data-sets and real ones. The experimental results demonstrate that the proposed EM variant has an increased capability to find the underlying model, while maintaining a low execution time.
Modeling the Injection-Locked Behavior of a Quantum Dash Semiconductor Laser

Using the conventional rate equations describing an injection-locked system, a novel modulation response function is derived, which implicitly incorporates nonlinear gain through the free-running relaxation oscillation frequency and damping rate of the slave laser. In this paper, it is shown that the model presented can be used to extract the characteristic parameters of the coupled system from experimental data. The number of fitting parameters in the model is reduced by determining the fundamental slave parameters through the conventional free-running response function; these parameters are considered to be constant during the curve-fitting of the injection-locked system. Furthermore, in order to reduce the number of possible solutions generated during the least-squares-fitting process, the remaining fitting parameters are tightly constrained based on the physical limits of the coupled system. By reducing the number of unknown fitting parameters and constraining the remaining terms, a stronger confidence in the extracted parameters is achieved. Using a series of response curves measured from an injection-locked quantum dash laser, characteristic parameters of the system are extracted and validity of the model is examined. The verified model is used to analyze the impact of the linewidth enhancement factor on the characteristics of the response function in the microwave domain.
Allele‐Specific Expression at the RET Locus in Blood and Gut Tissue of Individuals Carrying Risk Alleles for Hirschsprung Disease

RET common variants are associated with Hirschsprung disease (HSCR; colon aganglionosis), a congenital defect of the enteric nervous system. We analyzed a well‐known HSCR‐associated RET haplotype that encompasses linked alleles in coding and noncoding/regulatory sequences. This risk haplotype correlates with reduced level of RET expression when compared with the wild‐type counterpart. As allele‐specific expression (ASE) contributes to phenotypic variability in health and disease, we investigated whether RET ASE could contribute to the overall reduction of RET mRNA detected in carriers. We tested heterozygous neuroblastoma cell lines, ganglionic gut tissues (18 HSCR and 14 non‐HSCR individuals) and peripheral blood mononuclear cells (PBMCs; 16 HSCR and 14 non‐HSCR individuals). Analysis of the data generated by SNaPshot and Pyrosequencing revealed that the RET risk haplotype is significantly more expressed in gut than in PBMCs (P = 0.0045). No ASE difference was detected between patients and controls, irrespective of the sample type. Comparison of total RET expression levels between gut samples with and without ASE, correlated reduced RET expression with preferential transcription from the RET risk haplotype. Nonrandom RET ASE occurs in ganglionic gut regardless of the disease status. RET ASE should not be excluded as a disease mechanism acting during development.
Epigenetic inactivation of follistatin-like 1 mediates tumor immune evasion in nasopharyngeal carcinoma

Follistatin like-1 (FSTL1) is a secreted glycoprotein involved in a series of physiological and pathological processes. However, its contribution to the development of cancer, especially the pathogenesis of nasopharyngeal carcinoma (NPC), remains to be elucidated. We aimed to investigate the dysregulation of FSTL1 and its possible function in NPC. FSTL1 was frequently downregulated in NPC cell lines and primary tumor biopsies by promoter hypermethylation. Ectopic expression of FSTL1 significantly suppressed the colony formation, proliferation, migration and invasion ability of NPC cells and induced cell apoptosis. Overexpression of FSTL1 decreased the tumorigenicity of NPC cells in vivo. In addition, the proliferation of NPC cells in vitro was inhibited by treatment with soluble recombinant FSTL1 protein. The protein level of FSTL1 was decreased in primary NPC tumors and was associated with downregulated interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α). Furthermore, recombinant human FSTL1 protein induced secretion of IL-1β and TNF-α in macrophage cultures, therefore FSTL1 might activate macrophages and attenuate the immune evasion of NPC cells. In conclusion, the epigenetic downregulation of FSTL1 may suppress the proliferation and migration of NPC cells, leading to dysfunctional innate responses in surrounding macrophages.
From indexing the biomedical literature to coding clinical text: experience with MTI and machine learning approaches

This paper describes the application of an ensemble of indexing and classification systems, which have been shown to be successful in information retrieval and classification of medical literature, to a new task of assigning ICD-9-CM codes to the clinical history and impression sections of radiology reports. The basic methods used are: a modification of the NLM Medical Text Indexer system, SVM, k-NN and a simple pattern-matching method. The basic methods are combined using a variant of stacking. Evaluated in the context of a Medical NLP Challenge, fusion produced an F-score of 0.85 on the Challenge test set, which is considerably above the mean Challenge F-score of 0.77 for 44 participating groups.
Pre–Tissue Plasminogen Activator Blood Pressure Levels and Risk of Symptomatic Intracerebral Hemorrhage

Background and Purpose— From small pilot studies, uncontrolled pretreatment systolic blood pressure >185 mm Hg and diastolic blood pressure >110 mm Hg in patients with acute ischemic stroke were introduced in the National Institute of Neurological Diseases and Stroke rtPA Stroke Study as a contraindication for thrombolysis. We sought to determine if pretreatment blood pressure protocol violations in patients with acute ischemic stroke receiving intravenous tissue plasminogen activator are related to the subsequent risk of symptomatic intracranial hemorrhage (sICH). Methods— We reviewed medical records of consecutive ischemic stroke admissions treated with intravenous thrombolysis over a 10-year period at our tertiary care hospital. The National Institutes of Health Stroke Scale score on admission was used to determine baseline stroke severity. The closest documented blood pressure values to the time of tissue plasminogen activator bolus (range, 0 to 10 minutes) were considered as pretreatment blood pressure. Pretreatment blood pressure protocol violations were identified as systolic blood pressure >185 or diastolic blood pressure >110 mm Hg prebolus. sICH was defined as brain imaging evidence of intracranial hemorrhage with clinical worsening by the National Institutes of Health Stroke Scale score increase of ≥4 points. Results— Among 510 patients with ischemic stroke treated with intravenous tissue plasminogen activator (282 men; mean age, 65±15 years), sICH occurred in 31 patients (6.1%). Blood pressure protocol violations were present in 63 patients (12.4%) and they were more frequent in patients with sICH (26% versus 12%; P=0.019). After adjusting for demographic characteristics, onset-to-treatment time, baseline National Institutes of Health Stroke Scale, stroke risk factors and medications, pretreatment blood pressure protocol violations were independently associated with a higher likelihood of sICH (OR, 2.59; 95% CI, 1.07 to 6.25; P=0.034). Conclusions— These data support current guidelines advising not to use intravenous tissue plasminogen activator when pretreatment blood pressure exceeds the prespecified thresholds by showing that blood pressure protocol violations are independently associated with a higher likelihood of sICH.
Insulin and phorbol ester stimulate initiation factor eIF-4E phosphorylation by distinct pathways in Chinese hamster ovary cells overexpressing the insulin receptor.

We have developed a one-dimensional isoelectric focusing technique to measure changes in the steady-state phosphorylation of the cap-binding initiation factor, eIF-4E. We have used a Chinese hamster ovary cell line transfected with the human insulin receptor (CHO.T cells) to study the regulation of eIF-4E phosphorylation by insulin and other stimuli. Exposure of CHO.T cells to insulin, phorbol ester or serum resulted in a rapid increase (up to twofold) in eIF-4E phosphorylation. As a control, we have also performed experiments with the parental cell line, CHO.K1 cells, in which both serum and phorbol ester, but not nanomolar concentrations of insulin, produce similar changes in eIF-4E phosphorylation. We have used two complementary approaches to study the role of protein kinase C (PKC) in these responses: a highly specific inhibitor of PKC and down-regulation of PKC by prior treatment of the cells with phorbol ester. In CHO.T cells, both approaches indicate that PKC is required for the response to phorbol ester but that insulin and serum each increase eIF-4E phosphorylation by a mechanism(s) independent of this protein kinase. Similarly, PKC is necessary for the effects of phorbol ester, but not of serum, on eIF-4E phosphorylation in CHO.K1 cells. These data indicate that multiple signal transduction mechanisms are involved in the modulation of eIF-4E phosphorylation and the implications of these findings are discussed.
Aging and decision making: How aging affects decisions under uncertainty

In an aging society, it becomes more and more important to understand how aging affects decision making. Older adults have to face many situations that require consequential financial decisions. In the present study, we examined the effects of aging on decisions in two domains of uncertainty: risk and ambiguity. For this purpose, a group of young and older adults played a card game which was composed of risky and ambiguous conditions. In the risk condition, participants knew the probabilities to win or loose the game (i.e. full information), whereas in the ambiguous condition, these probabilities were unknown (thus, there was lack of information). When confronted with risky decisions, the behaviour of older and young adults (measured by the number of times participants chose a gamble instead of a sure amount of money) did not differ. In contrast, under ambiguity, there were significant age-effects in decision making: older people were less ambiguity-averse than young subjects. We conclude that there exist differences in uncertainty-processing between young and older adults, and discuss possible explanations of these differences.
A Review of Adversity, The Amygdala and the Hippocampus: A Consideration of Developmental Timing

A review of the human developmental neuroimaging literature that investigates outcomes following exposure to psychosocial adversity is presented with a focus on two subcortical structures – the hippocampus and the amygdala. Throughout this review, we discuss how a consideration of developmental timing of adverse experiences and age at measurement might provide insight into the seemingly discrepant findings across studies. We use findings from animal studies to suggest some mechanisms through which timing of experiences may result in differences across time and studies. The literature suggests that early life may be a time of heightened susceptibility to environmental stressors, but that expression of these effects will vary by age at measurement.
Evaluating Paratransgenesis as a Potential Control Strategy for African Trypanosomiasis

Genetic-modification strategies are currently being developed to reduce the transmission of vector-borne diseases, including African trypanosomiasis. For tsetse, the vector of African trypanosomiasis, a paratransgenic strategy is being considered: this approach involves modification of the commensal symbiotic bacteria Sodalis to express trypanosome-resistance-conferring products. Modified Sodalis can then be driven into the tsetse population by cytoplasmic incompatibility (CI) from Wolbachia bacteria. To evaluate the effectiveness of this paratransgenic strategy in controlling African trypanosomiasis, we developed a three-species mathematical model of trypanosomiasis transmission among tsetse, humans, and animal reservoir hosts. Using empirical estimates of CI parameters, we found that paratransgenic tsetse have the potential to eliminate trypanosomiasis, provided that any extra mortality caused by Wolbachia colonization is low, that the paratransgene is effective at protecting against trypanosome transmission, and that the target tsetse species comprises a large majority of the tsetse population in the release location.
Pegylated Interferon-α2a Inhibits Proliferation of Human Liver Cancer Cells In Vitro and In Vivo

Purpose We investigated the effects of pegylated interferon-α2a (PEG-IFN-α2a) on the growth of human liver cancer cells. Methods The effect of PEG-IFN-α2a on the proliferation of 13 liver cancer cell lines was investigated in vitro. Cells were cultured with medium containing 0–4,194 ng/mL of PEG-IFN-α2a, and after 1, 2, 3, or 4 days of culture, morphologic observation and growth assay were performed. After hepatocellular carcinoma (HCC) cells (HAK-1B and KIM-1) were transplanted into nude mice, various doses of PEG-IFN-α2a were subcutaneously administered to the mice once a week for 2 weeks, and tumor volume, weight, and histology were examined. Results PEG-IFN-α2a inhibited the growth of 8 and 11 cell lines in a time- and dose-dependent manner, respectively, although the 50% growth inhibitory concentrations of 7 measurable cell lines on Day 4 were relatively high and ranged from 253 ng/mL to 4,431 ng/mL. Various levels of apoptosis induction were confirmed in 8 cell lines. PEG-IFN-α2a induced a dose-dependent decrease in tumor volume and weight, and a significant increase of apoptotic cells in the tumor. Subcutaneous administration of clinical dose for chronic hepatitis C (3 μg/kg, 0.06 μg/mouse) was effective and induced about 30-50% reduction in the tumor volume and weight as compared with the control. Conclusions Although in vitro anti-proliferative effects of PEG-IFN-α2a were relatively weak, PEG-IFN-α2a induced strong anti-tumor effects on HCC cells in vivo. The data suggest potential clinical application of PEG-IFN-α2a for the prevention and treatment of HCC.
Decidability of the Logics of the Reflexive Sub-interval and Super-interval Relations over Finite Linear Orders

An interval temporal logic is a propositional, multi-modal logic interpreted over interval structures of partial orders. The semantics of each modal operator are given in the standard way with respect to one of the natural accessibility relations defined on such interval structures. In this paper, we consider the modal operators based on the (reflexive) sub-interval relation and the (reflexive) super-interval relation. We show that the satisfiability problems for the interval temporal logics featuring either or both of these modalities, interpreted over interval structures of finite linear orders, are all PSPACE-complete. These results fill a gap in the known complexity results for interval temporal logics.
Effectiveness of nurse-practitioner-delivered brief motivational intervention for young adult alcohol and drug use in primary care in South Africa: a randomized clinical trial.

AIMS To assess the effectiveness of brief motivational intervention for alcohol and drug use in young adult primary care patients in a low-income population and country. METHODS A randomized controlled trial in a public-sector clinic in Delft, a township in the Western Cape, South Africa recruited 403 patients who were randomized to either single-session, nurse practitioner-delivered Brief Motivational Intervention plus referral list or usual care plus referral list, and followed up at 3 months. RESULTS Although rates of at-risk alcohol use and drug use did not differ by treatment arm at follow-up, patients assigned to the Brief Motivational Intervention had significantly reduced scores on ASSIST (Alcohol, Smoking and Substance Involvement Screening Test) for alcohol-the most prevalent substance. CONCLUSION Brief Motivational Intervention may be effective at reducing at-risk alcohol use in the short term among low-income young adult primary care patients; additional research is needed to examine long-term outcomes.
Preparing for and Executing a Randomised Controlled Trial of Podoconiosis Treatment in Northern Ethiopia: The Utility of Rapid Ethical Assessment

Background Community-based randomized controlled trials are often complex pieces of research with significant challenges around the approach to the community, information provision, and decision-making, all of which are fundamental to the informed consent process. We conducted a rapid ethical assessment to guide the preparation for and conduct of a randomized controlled trial of podoconiosis treatment in northern Ethiopia. Methods A qualitative study was carried out in Aneded woreda, East Gojjam Zone, Amhara Regional State from August to September, 2013. A total of 14 In-depth Interviews (IDIs) with researchers, experts, and leaders, and 8 Focus Group Discussions (FGDs) involving 80 participants (people of both gender, with and without podoconiosis), were conducted. Interviews were carried out in Amharic. Data analysis was started alongside collection. Final data analysis used a thematic approach based on themes identified a priori and those that emerged during the analysis. Results Respondents made a range of specific suggestions, including that sensitisation meetings were called by woreda or kebele leaders or the police; that Health Extension Workers were asked to accompany the research team to patients’ houses; that detailed trial information was explained by someone with deep local knowledge; that analogies from agriculture and local social organisations be used to explain randomisation; that participants in the ‘delayed’ intervention arm be given small incentives to continue in the trial; and that key community members be asked to quell rumours arising in the course of the trial. Conclusion Many of these recommendations were incorporated into the preparatory phases of the trial, or were used during the course of the trial itself. This demonstrates the utility of rapid ethical assessment preceding a complex piece of research in a relatively research-naive setting.
The Localization of Human Cyclins B1 and B2 Determines Cdk1 Substrate Specificity and Neither Enzyme Requires Mek to Disassemble the Golgi Apparatus

In this paper, we show that substrate specificity is primarily conferred on human mitotic cyclin-dependent kinases (CDKs) by their subcellular localization. The difference in localization of the B-type cyclin–CDKs underlies the ability of cyclin B1–CDK1 to cause chromosome condensation, reorganization of the microtubules, and disassembly of the nuclear lamina and of the Golgi apparatus, while it restricts cyclin B2–CDK1 to disassembly of the Golgi apparatus. We identify the region of cyclin B2 responsible for its localization and show that this will direct cyclin B1 to the Golgi apparatus and confer upon it the more limited properties of cyclin B2. Equally, directing cyclin B2 to the cytoplasm with the NH2 terminus of cyclin B1 confers the broader properties of cyclin B1. Furthermore, we show that the disassembly of the Golgi apparatus initiated by either mitotic cyclin–CDK complex does not require mitogen-activated protein kinase kinase (MEK) activity.