Miracle-dz/UniFAR-FTUs huggingface dataset:
PANTHER version 6: protein sequence and function evolution data with expanded representation of biological pathways

PANTHER is a freely available, comprehensive software system for relating protein sequence evolution to the evolution of specific protein functions and biological roles. Since 2005, there have been three main improvements to PANTHER. First, the sequences used to create evolutionary trees are carefully selected to provide coverage of phylogenetic as well as functional information. Second, PANTHER is now a member of the InterPro Consortium, and the PANTHER hidden markov Models (HMMs) are distributed as part of InterProScan. Third, we have dramatically expanded the number of pathways associated with subfamilies in PANTHER. Pathways provide a detailed, structured representation of protein function in the context of biological reaction networks. PANTHER pathways were generated using the emerging Systems Biology Markup Language (SBML) standard using pathway network editing software called CellDesigner. The pathway collection currently contains ∼1500 reactions in 130 pathways, curated by expert biologists with authorship attribution. The curation environment is designed to be easy to use, and the number of pathways is growing steadily. Because the reaction participants are linked to subfamilies and corresponding HMMs, reactions can be inferred across numerous different organisms. The HMMs can be downloaded by FTP, and tools for analyzing data in the context of pathways and function ontologies are available at .
Out-of-Core Divisible Load Processing

In this paper, we analyze processing divisible loads in systems with a memory hierarchy. Divisible loads are computations that can be divided into parts of arbitrary sizes and these parts can be independently processed in a distributed system. The problem is to partition the load so that the total processing time, including communications and computations, is the shortest possible. Earlier works in the divisible load theory assumed distributed systems with a flat memory model. The dependence of the processing time on the size of the assigned load was assumed to be linear. A new mathematical model relaxing the above two assumptions is proposed in this article. We study distributed systems-which have both the hierarchical memory model and a piecewise linear dependence of the processing time on the size of the assigned load. Performance of such systems is modeled and evaluated. Finally, we compare the efficiency of distributed processing divisible loads in multiinstallment and out-of-core modes. Multiinstallment processing consists in sending multiple small chunks of the load to processors instead of a single chunk which needs external memory. It turns out that multiinstallment is an advantageous strategy for reasonably selected load chunks sizes.
The multiple lentigines syndrome.

Melanocytes are derived in the embryo from the neuroectoderm. They are responsible in part for formation of the inner ear. There is a frequent association of congenital pigmentary abnormalities with hearing loss and neurologic diseases. Examination of patients with inherited pigmentary disorders might reveal that the genetic defect affects all tissues of neuroectodermal origin. The findings in our patient are consistent with this hypothesis. Electron microscopic findings of the lentigines are reported.
Routing Techniques for Gate Array

This paper describes the routing techniques used for a Hughes internally developed high-density silicon-gate bulk CMOS gate array family. This layout software can be easily adapted to different array sizes and/or technologies (e.g., bipolar) through a change of parameters. A routing model and hierarchical decomposition schemes are presented to address the routability issue. More specifically, this paper focuses on the formulation and analysis of global routing and vertical assignment problems and gives a systematic breakdown of the routing task into well-defined subtasks. Instead of performing sequential routing, techniques and formulations are introduced to achieve a high degree of order independency in all subtasks. In routing subtasks where iterations are required, independent selection and interconnection are performed to avoid order dependency in typical routing problems. Implementation results are provided to indicate the efficiency of the system.
Performance of Sequential Imputation Method in Multilevel Applications

In missing-data problems complicated not only by the underlying data-generating mechanism (e.g. multi-stage surveys) but also skip patterns, censored items and a diverse set of variable types, a variable-by-variable imputation strategy has been increasingly popular among practitioners. While this approach offers certain advantages, it does not necessarily follow a conventional joint modeling approach. Our work assesses the performance and compatibility of sequential approach to a joint modeling approach in multilevel settings. This sequential approach uses a set of hierarchical regression models each of which follows the appropriate format for the underlying variable subject to missingness. Computational techniques used to approximate the conditional posterior predictive distributions are based on Markov Chain Monte Carlo and/or numerical integration techniques to overcome the problem of intractability. We present a simulation study assessing the performance of the sequential approach. In most realistic applications, our simulations suggest that the sequential method lead to well-calibrated estimates and in some settings the performance is even better than the more conventional methods with well-defined joint model in some scenarios.
Effective Deep Memory Networks for Distant Supervised Relation Extraction

Distant supervised relation extraction (RE) has been an effective way of ﬁnding novel relational facts from text without labeled training data. Typically it can be formalized as a multi-instance multi-label problem. In this paper, we introduce a novel neural approach for distant supervised RE with special focus on attention mechanisms. Unlike the feature-based logistic regression model and compositional neural models such as CNN, our approach includes two major attention-based memory components, which are capable of explicitly capturing the importance of each context word for modeling the representation of the entity pair, as well as the intrinsic dependencies between relations. Such importance degree and dependency relationship are calculated with multiple computational layers, each of which is a neural attention model over an ex-ternal memory. Experiment on real-world datasets shows that our approach performs signiﬁcantly and consistently better than various baselines.
Weight loss after bariatric surgery improves aortic elastic properties and left ventricular function in individuals with morbid obesity: a 3-year follow-up study

Objective To investigate whether weight loss after bariatric surgery (gastric bypass) is associated with changes in aortic function (an important determinant of left ventricular function) and in left ventricular function, in morbidly obese individuals 3 and 36 months after surgery. Methods We used echocardiography to evaluate 60 obese individuals [body mass index (BMI) > 40 kg/m2] who underwent surgery and 20 obese individuals who neither underwent surgery nor lost weight, at baseline and at 3 and 36 months of follow-up, and 40 lean individuals (BMI < 25 kg/m2) of similar age, sex and risk factors, at baseline. We measured aortic strain, distensibility, stiffness index, pressure–strain modulus and Doppler indices of left ventricular diastolic dysfunction (ratio of peak early to peak atrial flow velocities, isovolumic relaxation time and deceleration time). Results Baseline aortic function and Doppler diastolic indices were impaired in obese individuals compared with those who were lean (P < 0.05). During 3 and 36 months of follow-up, BMI and left ventricular diastolic diameter, volume, mass and wall thickness were reduced, and indices of aortic function and left ventricular diastolic function were normalized, in obese individuals after surgery [aortic distensibility (cm2 × dyn−1 × 10−6): 1.9 before surgery, 3.4 at 3 months after surgery and 4.3 at 3 years after surgery, compared with 3.36 in lean controls; P < 0.01], but not in those who did not lose weight. The reduction in BMI after surgery was related to the concomitant improvement in indices of aortic function (P < 0.01) and isovolumic relaxation time (P < 0.05) after adjustment for age, sex and concomitant reduction in blood pressure, lipids and glucose concentrations. Conclusion Weight reduction after bariatric surgery normalizes aortic function, reduces left ventricular hypertrophy and, thus, improves left ventricular diastolic function in morbidly obese individuals over a 3-year period of follow-up.
Serum Ferritin is a Cost-effective Laboratory Marker for Hemophagocytic Lymphohistiocytosis in the Developing World

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease in children and presents many diagnostic difficulties. Without prompt intervention, the disease typically runs a rapidly fatal course. Diagnostic criteria were proposed by the Histiocyte Society in 1991 and have since been modified. Included in these criteria is a ferritin level >500 mcg/L2. Although not diagnostic, a high ferritin level is highly suggestive of HLH. Serum ferritin assays are more accessible and cost-effective compared with other biochemical markers, particularly in resource-limited settings. Fifteen patients with HLH were treated at Red Cross War Memorial Children’s Hospital between 1991 and 2010. Hyperferritinemia was a consistently reliable finding (93%) compared with either serum fibrinogen or triglycerides, which were elevated in only half of the patients. It is our contention that analysis of a complete blood count and serum ferritin (in addition to clinical criteria and tissue examination of marrow and/or cerebrospinal fluid) is probably the single most cost-effective and clinically helpful means to make the diagnosis of HLH when laboratory access is limited.
Requirement of Multiple cis-Acting Elements in the Human Cytomegalovirus Major Immediate-Early Distal Enhancer for Viral Gene Expression and Replication

ABSTRACT We have shown previously that the human cytomegalovirus (HCMV) major immediate-early (MIE) distal enhancer is needed for MIE promoter-dependent transcription and viral replication at low multiplicities of infection (MOI). To understand how this region works, we constructed and analyzed a series of HCMVs with various distal enhancer mutations. We show that the distal enhancer is composed of at least two parts that function independently to coordinately activate MIE promoter-dependent transcription and viral replication. One such part is contained in a 47-bp segment that has consensus binding sites for CREB/ATF, SP1, and YY1. At low MOI, these working parts likely function in cis to directly activate MIE gene expression, thus allowing viral replication to ensue. Three findings support the view that these working parts are likely cis-acting elements. (i) Deletion of either part of a bisegmented distal enhancer only slightly alters MIE gene transcription and viral replication. (ii) Reversing the distal enhancer’s orientation largely preserves MIE gene transcription and viral replication. (iii) Placement of stop codons at −300 or −345 in all reading frames does not impair MIE gene transcription and viral replication. Lastly, we show that these working parts are dispensable at high MOI, partly because of compensatory stimulation of MIE promoter activity and viral replication that is induced by a virion-associated component(s) present at a high viral particle/cell ratio. We conclude that the distal enhancer is a complex multicomponent cis-acting region that is required to augment both MIE promoter-dependent transcription and HCMV replication.
p 90 ribosomal S 6 kinase 3 contributes to cardiac insufficiency in-tropomyosin Glu 180 Gly transgenic mice

Catherine L. Passariello, Marjorie Gayanilo, Michael D. Kritzer, Hrishikesh Thakur, Zoharit Cozacov, Francesca Rusconi, David Wieczorek, Michael Sanders, Jinliang Li, and Michael S. Kapiloff Cardiac Signal Transduction and Cellular Biology Laboratory, Interdisciplinary Stem Cell Institute, Departments of Pediatrics and Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida; and Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio
Role of Aryl Hydrocarbon Receptor-mediated Induction of the CYP1 Enzymes in Environmental Toxicity and Cancer*

The mammalian CYP1A1, CYP1A2, and CYP1B1 genes (encoding cytochromes P450 1A1, 1A2, and 1B1, respectively) are regulated by the aromatic hydrocarbon receptor (AHR). The CYP1 enzymes are responsible for both metabolically activating and detoxifying numerous polycyclic aromatic hydrocarbons (PAHs) and aromatic amines present in combustion products. Many substrates for CYP1 enzymes are AHR ligands. Differences in AHR affinity between inbred mouse strains reflect variations in CYP1 inducibility and clearly have been shown to be associated with differences in risk of toxicity or cancer caused by PAHs and arylamines. Variability in the human AHR affinity exists, but differences in human risk of toxicity or cancer related to AHR activation remain unproven. Mouse lines having one or another of the Cyp1 genes disrupted have shown paradoxical effects; in the test tube or in cell culture these enzymes show metabolic activation of PAHs or arylamines, whereas in the intact animal these enzymes are sometimes more important in the role of detoxification than metabolic potentiation. Intact animal data contradict pharmaceutical company policies that routinely test drugs under development; if a candidate drug shows CYP1 inducibility, further testing is generally discontinued for fear of possible toxic or carcinogenic effects. In the future, use of “humanized” mouse lines, containing a human AHR or CYP1 allele in place of the orthologous mouse gene, is one likely approach to show that the AHR and the CYP1 enzymes in human behave similarly to that in mouse.
COLLECTION : TRANSLATIONAL IMPACT OF DROSOPHILA Neurodegeneration in a Drosophila model of adrenoleukodystrophy : the roles of the Bubblegum and Double bubble acyl-CoA synthetases

Debilitating neurodegenerative conditions with metabolic origins affect millions of individuals worldwide. Still, for most of these neurometabolic disorders there are neither cures nor diseasemodifying therapies, and novel animal models are needed for elucidation of disease pathology and identification of potential therapeutic agents. To date, metabolic neurodegenerative disease has been modeled in animals with only limited success, in part because existing models constitute analyses of single mutants and have thus overlooked potential redundancy within metabolic gene pathways associated with disease. Here, we present the first analysis of a very-long-chain acyl-CoA synthetase (ACS) double mutant. We show that the Drosophila bubblegum (bgm) and double bubble (dbb) genes have overlapping functions, and that the consequences of double knockout of both bubblegum and double bubble in the fly brain are profound, affecting behavior and brain morphology, and providing the best paradigm to date for an animal model of adrenoleukodystrophy (ALD), a fatal childhood neurodegenerative disease associated with the accumulation of very-long-chain fatty acids. Using this more fully penetrant model of disease to interrogate brain morphology at the level of electron microscopy, we show that dysregulation of fatty acid metabolism via disruption of ACS function in vivo is causal of neurodegenerative pathologies that are evident in both neuronal cells and their supporting cell populations, and leads ultimately to lytic cell death in affected areas of the brain. Finally, in an extension of our model system to the study of human disease, we describe our identification of an individual with leukodystrophy who harbors a rare mutation in SLC27a6 (encoding a very-long-chain ACS), a human homolog of bgm and dbb.
Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease.

BACKGROUND Individuals with chronic bronchitis or chronic obstructive pulmonary disease (COPD) may suffer recurrent exacerbations with an increase in volume and/or purulence of sputum. Because of the personal and healthcare costs associated with exacerbations, any therapy that reduces the number of exacerbations is useful. There is a marked difference between countries in terms of prescribing of mucolytics depending on whether or not they are perceived to be effective. OBJECTIVES To assess the effects of oral mucolytics in adults with stable chronic bronchitis or COPD. SEARCH STRATEGY We searched the Cochrane Airways Group Specialised Register and reference lists of articles on eight separate occasions, the most recent being in September 2008. SELECTION CRITERIA Randomised trials that compared oral mucolytic therapy with placebo for at least two months in adults with chronic bronchitis or COPD. We excluded studies of people with asthma and cystic fibrosis. DATA COLLECTION AND ANALYSIS One review author extracted data. We contacted study authors and drug companies for missing information. MAIN RESULTS Twenty-eight trials involving 7042 participants were included. Compared with placebo, there was a significant reduction in the number of exacerbations per patient with oral mucolytics (weighted mean difference (WMD) -0.04 per month, 95% confidence interval -0.05 to -0.03). Using a weighted annualised rate of exacerbations in the control patients of 2.4 per year, this is a 21% reduction. The number of days of disability also fell (WMD -0.56, 95% confidence interval (CI) -0.77 to -0.35). One recent study has shown that the benefit may apply only to patients not already receiving inhaled corticosteroids. The number of patients who remained exacerbation-free was greater in the mucolytic group (odds ratio (OR) 1.93 (95% CI 1.71 to 2.17)). There is no strong evidence of improvement in lung function and treatment is not associated with any increase in adverse effects. Patients on mucolytics may be less likely to be hospitalised during the study period. AUTHORS' CONCLUSIONS In participants with chronic bronchitis or COPD, treatment with mucolytics was associated with a small reduction in acute exacerbations and a reduction in total number of days of disability. Benefit may be greater in individuals who have frequent or prolonged exacerbations, or those who are repeatedly admitted to hospital with exacerbations with COPD. Mucolytics should be considered for use, through the winter months at least, in patients with moderate or severe COPD in whom inhaled corticosteroids (ICS) are not prescribed.
Tinnitus psychopharmacology: A comprehensive review of its pathomechanisms and management

Background: Subjective tinnitus is a frequent, impairing condition, which may also cause neurotransmitter imbalance at the cochlea. Psychopharmacologic agents, although not being the first-line treatment for tinnitus, may modulate cochlear neurotransmission, thereby influencing the subjective tinnitus experience. Method: A comprehensive review of MEDLINE literature (from January 1990–January 2010) was performed searching for: “tinnitus”, major classes of psychopharmacological agents, and psychiatric disorders. The most relevant clinical evidence is reported briefly along with a concise description of the main neurotransmitters purported to be involved in tinnitus, in order to provide the reader with a rational evaluation of tinnitus therapy with psychopharmacological agents. Results: Although strong methodological issues limit the reliability of the current results, a broad number of psychopharmacological agents have already been considered for tinnitus, both as candidate triggers or potential therapies. Conclusions: Selected psychopharmacological drugs may play a role in the clinical management of this disorder. While the rational use of these agents for the treatment of tinnitus should not be overlooked, research should be undertaken on their neuromodulating actions at the cochlea.
Phase I trial of buthionine sulfoximine in combination with melphalan in patients with cancer.

PURPOSE AND METHODS Resistance to alkylating agents and platinum compounds is associated with elevated levels of glutathione (GSH). Depletion of GSH by buthionine sulfoximine (BSO) restores the sensitivity of resistant tumors to melphalan in vitro and in vivo. In a phase I trial, each patient received two cycles as follows: BSO alone intravenously (i.v.) every 12 hours for six doses, and 1 week later the same BSO as cycle one with melphalan (L-PAM) 15 mg/m2 i.v. 1 hour after the fifth dose. BSO doses were escalated from 1.5 to 17 g/m2 in 41 patients. RESULTS The only toxicity attributable to BSO was grade I or II nausea/vomiting in 50% of patients. Dose-related neutropenia required an L-PAM dose reduction to 10 mg/m2 at BSO 7.5 g/m2. We measured GSH in peripheral mononuclear cells (PMN), and in tumor biopsies when available, at intervals following BSO dosing. In PMNs, GSH content decreased over 36 to 72 hours to reach a nadir on day 3; at the highest dose, recovery was delayed beyond day 7. The mean PMN GSH nadirs were approximately 10% of control at BSO doses > or = 7.5 g/m2; at 13 and 17 g/m2, all but two patients had nadir values in this range. GSH was depleted in sequential tumor biopsies to a variable extent, but with a similar time course. At BSO doses > or = 13 g/m2, tumor GSH was < or = 20% of starting values on day 3 in five of seven patients; recovery had not occurred by day 5. We measured plasma concentrations of R- and S-BSO by high-performance liquid chromatography (HPLC) in 22 patients throughout the dosing period. Total-body clearance (CLt) and volume of distribution at steady-state (Vss) for both isomers were dose-independent. The CLt of S-BSO was significantly less than that of R-BSO at all doses, but no significant differences in Vss were observed between the racemates. Harmonic mean half-lives were 1.39 hours and 1.89 hours for R-BSO and S-BSO, respectively. CONCLUSION A biochemically appropriate dose of BSO for use on this schedule is 13 g/m2, which will be used in phase II trials to be conducted in ovarian cancer and melanoma.
Sketching Word Vectors Through Hashing

We propose a new fast word embedding technique using hash functions. The method is a derandomization of a new type of random projections: By disregarding the classic constraint used in designing random projections (i.e., preserving pairwise distances in a particular normed space), our solution exploits extremely sparse non-negative random projections. Our experiments show that the proposed method can achieve competitive results, comparable to neural embedding learning techniques, however, with only a fraction of the computational complexity of these methods. While the proposed derandomization enhances the computational and space complexity of our method, the possibility of applying weighting methods such as positive pointwise mutual information (PPMI) to our models after their construction (and at a reduced dimensionality) imparts a high discriminatory power to the resulting embeddings. Obviously, this method comes with other known benefits of random projection-based techniques such as ease of update.
Optimal on-line estimation of the size of a dynamic multicast group

We propose an efficient on-line estimation algorithm for determining the size of a dynamic multicast group. By using diffusion approximation and a Kalman filter, we derive an estimator that minimizes the mean square of the estimation error. As opposed to previous studies, where the size of the multicast group is supposed to be fixed throughout the estimation procedure, we consider a dynamic estimation scheme that updates the estimation at every observation step. The robustness of our estimator to violation of the assumptions under which it has been derived is addressed via simulations. Further validations of our approach are carried out on real audio traces.