Miracle-dz/UniFAR-FTUs huggingface dataset:
To fold or expand—a charged question

It is no secret anymore that many proteins “defy” the common paradigm and do not fold to a well-defined 3D structure under native conditions. These are the so-called intrinsically disordered proteins (IDPs) (1). Some of these proteins do fold upon binding to a target (2), whereas others do not seem to fold under any known conditions. Much has been written in recent years about the connection between the folding behavior of IDPs and their activity. Furthermore, it was recognized that proteins belonging to this group are in general characterized by low hydrophobicity and high charge density (3); but are there any structural characteristics that might help us to understand the differences among various IDPs? An article by Muller-Spath, Soranno et al. (4) in PNAS proposes a correlation between the charge density and the overall dimensions of IDPs. The authors perform single-molecule fluorescence resonance energy transfer (FRET) spectroscopy on diffusing molecules. From the measured mean FRET efficiency they are able to compute the radius of gyration (Rg) of the molecules as a function of chemical denaturant concentration. The proteins studied include one stably folded protein (the globular cold shock protein CspTm) and two IDPs (the N-terminal domain of HIV-1 integrase, which folds upon binding of a zinc ion, and human prothymosin α). As is now well established (5), all three proteins gradually collapse when denaturant concentration is lowered. Surprisingly, the authors find that in the case of the two IDPs, Rg grows again as the concentration of the ionic denaturant guanidinium chloride is lowered below 1 M. They conclude that this is due to “release” of the proteins from electrostatic screening, because the extent of the observed expansion in buffer correlates well with the mean net charge on each chain.
A comparative clinical trial of adriamycin and 5‐fluorouracil in advanced prostatic cancer: Prognostic factors and response

In patients with metastatic hormone‐relapsed adenocarcinoma of the prostate, adriarnycin was compared to 5‐fluorouracil in a randomized trial in 99 patients and adriamycin alone was studied in an open trial in 48 patients. Response to adriamycin was superior as judged by response of measurable disease (25 vs 8%; P <0.05) and survival (median 29 vs 24 weeks; Cox analysis, P <0.03), but comparable as judged by acid phosphatase response. Ambulatory status and site of metastases influenced rate of response to chemotherapy. Activity level, site of metastases, weight loss, and the symptom of protein aversion were prognostic factors for survival. Hematologic and gastrointestinal toxicity were frequent but were tolerated satisfactorily. Adriamycin therapy may be beneficial in patients with prostatic cancer after hormone therapy.
Effect of endovascular reperfusion in relation to site of arterial occlusion

Objective: To assess whether the association between reperfusion and improved clinical outcomes after stroke differs depending on the site of the arterial occlusive lesion (AOL). Methods: We pooled data from Solitaire With the Intention for Thrombectomy (SWIFT), Solitaire FR Thrombectomy for Acute Revascularisation (STAR), Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study 2 (DEFUSE 2), and Interventional Management of Stroke Trial (IMS III) to compare the strength of the associations between reperfusion and clinical outcomes in patients with internal carotid artery (ICA), proximal middle cerebral artery (MCA) (M1), and distal MCA (M2/3/4) occlusions. Results: Among 710 included patients, the site of the AOL was the ICA in 161, the proximal MCA in 389, and the distal MCA in 160 patients (M2 = 131, M3 = 23, and M4 = 6). Reperfusion was associated with an increase in the rate of good functional outcome (modified Rankin Scale [mRS] score 0–2) in patients with ICA (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.7–7.2) and proximal MCA occlusions (OR 6.2, 95% CI 3.8–10.2), but not in patients with distal MCA occlusions (OR 1.4, 95% CI 0.8–2.6). Among patients with M2 occlusions, a subset of the distal MCA cohort, reperfusion was associated with excellent functional outcome (mRS 0–1; OR 2.2, 95% CI 1.0–4.7). Conclusions: The association between endovascular reperfusion and better clinical outcomes is more profound in patients with ICA and proximal MCA occlusions compared to patients with distal MCA occlusions. Because there are limited data from randomized controlled trials on the effect of endovascular therapy in patients with distal MCA occlusions, these results underscore the need for inclusion of this subgroup in future endovascular therapy trials.
Cigarette smoking affects oxidative protein folding in endoplasmic reticulum by modifying protein disulfide isomerase

The endoplasmic reticulum (ER) stress response (ERSR) and associated protein aggregation, is under investigation for its role in human diseases, including chronic obstructive pulmonary disease (COPD) where cigarette smoking (CS) is a risk factor for disease development. Our hypothesis states that CS‐associated oxidative stress interferes with oxidative protein folding in the ER and elicits ERSR. We investigated ERSR induction following acute CS exposure and delineated mechanisms of CS‐induced ERSR. Lung lysates from mice exposed or not to one cigarette were tested for activation of the ERSR. Up to 4‐fold increase in phosphorylation of eIF2α and nuclear form of ATF6 was detected in CS‐exposed animals. CS affected the formation of disulfide bonds through excessive posttranslational oxidation of protein disulfide isomerase (PDI). Increased amounts of complexes between PDI and its client proteins persisted in CS‐exposed samples. BiP was not a constituent of these complexes, demonstrating the specificity of the early effects of CS exposure on ER. Disturbances in protein folding were accompanied by changes in the organization of ER network and ER exit sites. Our results provide evidence that ERSR is induced early in response to CS exposure and identifies the first known ER‐resident target of CS PDI, demonstrating that CS affects oxidative protein folding. —Kenche, H. , Baty, C. J., Vedagiri, K. , Shapiro, S. D. , Blumental‐Perry, A. Cigarette smoking affects oxidative protein folding in endoplasmic reticulum by modifying protein disulfide isomerase. FASEB J. 27, 965–977 (2013). www.fasebj. org
Summarization via Submodular and Convex Optimization

We consider the problem of subset selection in the online setting, where data arrive incrementally. Instead of storing and running subset selection on the entire dataset, we propose an incremental subset selection framework that, at each time instant, uses the previously selected set of representatives and the new batch of data in order to update the set of representatives. We cast the problem as an integer binary optimization minimizing the encoding cost of the data via representatives regularized by the number of selected items. As the proposed optimization is, in general, NP-hard and non-convex, we study a greedy approach based on unconstrained submodular optimization and also propose an efficient convex relaxation. We show that, under appropriate conditions, the solution of our proposed convex algorithm achieves the global optimal solution of the non-convex problem. Our results also address the conventional problem of subset selection in the offline setting, as a special case. By extensive experiments on the problem of video summarization, we demonstrate that our proposed online subset selection algorithms perform well on real data, capturing diverse representative events in videos, while they obtain objective function values close to the offline setting.
Cost-effectiveness analysis of peginterferon beta-1a compared with interferon beta-1a and glatiramer acetate in the treatment of relapsing-remitting multiple sclerosis in the United States

Abstract Objective Peginterferon beta-1a 125 mcg, administered subcutaneously (SC) every 2 weeks, a new disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS), was approved by the US Food and Drug Administration in 2014. This study assesses the cost-effectiveness of peginterferon beta-1a vs interferon beta-1a (44 mcg SC 3 times per week) and glatiramer acetate (20 mg SC once-daily) in the treatment of RRMS from the perspective of a US payer over 10 years. Methods A Markov cohort economic model was developed for this analysis. The model predicts disability progression, occurrence of relapses and other adverse events and translates them into quality-adjusted life years (QALYs) and costs. Natural history data were obtained from the placebo arm of the ADVANCE trial of peginterferon beta-1a, the London Ontario (Canada) database and a large population-based MS survey. Comparative efficacy of each DMT vs placebo was obtained from a network meta-analysis. Costs (in 2014 US dollars) were sourced from public databases and literature. Clinical and economic outcomes were discounted at 3% per year. Results Over 10 years, peginterferon beta-1a was dominant (i.e., more effective and less costly), with cost-savings of $22,070 and additional 0.06 QALYs when compared with interferon beta-1a 44 mcg and with cost-savings of $19,163 and 0.07 QALYs gained when compared with glatiramer acetate 20 mg. Results were most sensitive to variations in the treatment effect of each DMT, treatment acquisition costs of each DMT and the time horizon. Probabilistic sensitivity analyses indicated that peginterferon beta-1a remains dominant in >90% of 5,000 replications compared with either DMTs. Conclusion This analysis suggests that long-term treatment with peginterferon beta-1a improves clinical outcomes at reduced costs compared with interferon beta-1a 44 mcg and glatiramer acetate 20 mg and should be a valuable addition to managed care formularies for treating patients with RRMS.
CLINICEvaluation of Exercise-Induced Bronchospasm Assessed by Peak Flow Meter in Obese Adolescents

Introduction: Children and adolescents who are overweight have a higher prevalence of exerciseinduced bronchospasm (EIB), as compared to eutrophics. Spirometry and peak flow meter are important evaluation methods of lung function. However, the applicability of the peak expiratory flow (peak flow meter) in the detection of EIB in children and adolescents who are overweight is not known, hence the development of this research. Objectives: To evaluate and compare the onset of exercise-induced bronchospasm (EIB) in children and adolescents non-asthmatic who are overweight, evaluated by spirometry and the peak flow meter (PEF). Methods: The study included 39 volunteers above the 85th percentile (OB) and 30 normal weight (EU), with the age of 8 to 15 years. The evaluation of lung function before and after bronchial provocation test was performed by spirometry and peak flow meter, according to the protocol of Del Río-Navarro et al, (2000). The EIB was considered positive when the volunteer showed a reduction ≥ 10% of baseline FEV1 or ≥ 20% reduction in PEF PFM and/or PEFE. Results: The detection of the BIE, the prevalence of obese group was 26% measured by peak flow meter (PEFPFM) and 23% for FEV1. The time of the BIE occurred with the first 15 minutes post-exercise in both parameters: (PFEPFM) and FEV1. Conclusion: The obese volunteers presented similar time and prevalence of EIB, when evaluated by both methods of pulmonary assessment. The easy handling and low cost from this method created greater accessibility for the general population from the peak flow meter, which shows its importance as part of an educational program in the initial diagnosis of EIB in large airway caliber.
A Unified Framework For Water Erosion And Deposition Equations

Two modeling frameworks have been developed to describe and predict soil erosion and sediment deposition in recent years. The first is based on the concept of transport capacity. Deposition occurs only when the transport capacity is exceeded. This approach has been implemented in WEPP (Water Erosion Prediction Project) and several other physically based erosion prediction models. An alternative approach is based on simultaneous erosion and deposition. Net erosion or deposition is seen as a result of the dynamic interactions among all processes involved. The simultaneous erosion and deposition approach lays the foundation for GUEST (Griffith University Erosion System Template) and for recent studies of multi-size sediment deposition. This paper uses the original governing equations for WEPP and GUEST to represent the two approaches to water erosion and deposition modeling. The paper shows analytically that the two sets of governing equations, while vastly different in their appearance, share an identical structure, and thus can be reduced to a common set of equations unifying both approaches. The unified framework involves four terms: (i) sediment concentration at the transport limit, (ii) flow detachment, (iii) sedimentation because of gravity, (iv) a rainfall-driven sediment source term. The two modeling frameworks show only minor differences in how these four terms are formulated. Analytical solutions to the unified erosion and deposition equations show that the characteristic length for erosion is the ratio of maximum sediment discharge to maximum rate of detachment, and the characteristic length for deposition is the ratio of minimum sediment discharge to minimum rate of deposition, or simply the ratio of unit discharge to fall velocity. The paper clarifies and simplifies the current approaches to erosion and deposition modeling.
Fast Top-$\boldsymbol{k}$ Area Topics Extraction with Knowledge Base

What are the most popular research topics in Artificial Intelligence (AI)? We formulate the problem as extracting top-$k$ topics that can best represent a given area with the help of knowledge base. We theoretically prove that the problem is NP-hard and propose an optimization model, FastKATE, to address this problem by combining both explicit and latent representations for each topic. We leverage a large-scale knowledge base (Wikipedia) to generate topic embeddings using neural networks and use this kind of representations to help capture the representativeness of topics for given areas. We develop a fast heuristic algorithm to efficiently solve the problem with a provable error bound. We evaluate the proposed model on three real-world datasets. Experimental results demonstrate our model's effectiveness, robustness, real-timeness (return results in $<1$s), and its superiority over several alternative methods.
A deterministic simulation modeling & analysis for the improvement of signal-to-noise ratio (SNR) based on ambient noise sources in underwater acoustic communication channel

This paper encompasses the sensitivity of SNR due to ambient noise sources individually using gradient method. The Gradient method has its own significance in the mathematical modeling and the purpose of using this method is of two fold; First, it gives the sensitivity of selected dependent variable with respect to the small and systematic changes in the independent variables separately or compositely in an equation. Second, it helps to determine a way to search for the optimal region or optimal values of the independent variables. Hence, this paper is intended to highlight the optimal region in order to determine a direction for the improvement of SNR in an underwater acoustic communication channel. In this paper, the gradient vectors of SNR have been modeled in MATLAB keeping in consideration the parameters as turbulence, shipping activities, wind and heat involved in underwater acoustic communication channel. The input model of SNR has been kept devoid of probability theory and uses some statistical approximations of underwater acoustic noise. Due to the absence of randomness in the variables of input model of SNR, the model output offers no uncertainties; hence giving a deterministic simulation model of the gradient vectors.
The influence of discrepant imaging judgements on the classification of axial spondyloarthritis is limited: a replication in the SpondyloArthritis Caught Early (SPACE) cohort

Sacroiliitis on imaging is important in the diagnosis and classification of patients with axial spondyloarthritis (axSpA). In the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axSpA, sacroiliitis is defined as either radiographic sacroiliitis (X-SI) according to the modified New York (mNY) criteria or active inflammation on MRI sacroiliac joints (MRI-SI) highly suggestive of axSpA (ASAS definition). 1–4 According to the ASAS criteria, patients with chronic back pain are classified via the imaging arm when sacroiliitis on MRI-SI or X-SI plus ≥1 spondyloarthritis (SpA) feature is present, or via the clinical arm where ≥2 SpA features in addition to Human Leukocyte Antigen B27 (HLA-B27) have to be present. While local clinicians can interpret imaging of the sacroiliac joints in the context of clinical information, central readers of research studies …
Heterogeneous behavior of metalloproteins toward metal ion binding and selectivity: insights from molecular dynamics studies

About one-third of the existing proteins require metal ions as cofactors for their catalytic activities and structural complexities. While many of them bind only to a specific metal, others bind to multiple (different) metal ions. However, the exact mechanism of their metal preference has not been deduced to clarity. In this study, we used molecular dynamics (MD) simulations to investigate whether a cognate metal (bound to the structure) can be replaced with other similar metal ions. We have chosen seven different proteins (phospholipase A2, sucrose phosphatase, pyrazinamidase, cysteine dioxygenase (CDO), plastocyanin, monoclonal anti-CD4 antibody Q425, and synaptotagmin 1 C2B domain) bound to seven different divalent metal ions (Ca2+, Mg2+, Zn2+, Fe2+, Cu2+, Ba2+, and Sr2+, respectively). In total, 49 MD simulations each of 50 ns were performed and each trajectory was analyzed independently. Results demonstrate that in some cases, cognate metal ions can be exchanged with similar metal ions. On the contrary, some proteins show binding affinity specifically to their cognate metal ions. Surprisingly, two proteins CDO and plastocyanin which are known to bind Fe2+ and Cu2+, respectively, do not exhibit binding affinity to any metal ion. Furthermore, the study reveals that in some cases, the active site topology remains rigid even without cognate metals, whereas, some require them for their active site stability. Thus, it will be interesting to experimentally verify the accuracy of these observations obtained computationally. Moreover, the study can help in designing novel active sites for proteins to sequester metal ions particularly of toxic nature.
Phytochelatin Synthases of the Model Legume Lotus japonicus. A Small Multigene Family with Differential Response to Cadmium and Alternatively Spliced Variants1[OA]

The biosynthesis of phytochelatins and homophytochelatins has been studied in nodulated plants of the model legume Lotus (Lotus japonicus). In the first 6 to 24 h of treatment with cadmium (Cd), roots started to synthesize elevated amounts of both polypeptides, with a concomitant increase of glutathione and a decrease of homoglutathione, indicating the presence of active phytochelatin synthase (PCS) genes. Screening of transformation-competent artificial chromosome libraries allowed identification of a cluster of three genes, LjPCS1, LjPCS2, and LjPCS3, which were mapped at 69.0 cM on chromosome 1. The genes differ in exon-intron composition and responsiveness to Cd. Gene structures and phylogenetic analysis of the three protein products, LjPCS1-8R, LjPCS2-7N, and LjPCS3-7N, are consistent with two sequential gene duplication events during evolution of vascular plants. Two sites for alternative splicing in the primary transcripts were identified. One of them, involving intron 2 of the LjPCS2 gene, was confirmed by the finding of the two predicted mRNAs, encoding LjPCS2-7R in roots and LjPCS2-7N in nodules. The amino acid sequences of LjPCS2-7R (or LjPCS2-7N) and LjPCS3-7N share 90% identity, but have only 43% to 59% identity with respect to the typical PCS1 enzymes of Lotus and other plants. The unusual LjPCS2-7N and LjPCS3-7N proteins conferred Cd tolerance when expressed in yeast (Saccharomyces cerevisiae) cells, whereas the alternatively spliced form, LjPCS2-7R, differing only in a five-amino acid motif (GRKWK) did not. These results unveil complex regulatory mechanisms of PCS expression in legume tissues in response to heavy metals and probably to other developmental and environmental factors.
The Fundamentals of Kansei Engineering and a Methodological Problem: Human Internal Information and Empathy

Researches in Biometrics (B. M.) and Kansei engineering (K. E.) commonly utilize biological or physiological data as their major means. Therefore, it seems plausible to expect meaningful cooperation between B. M. and K. E. Aiming at exploring a possibility to materialize such an expectation, in the 1st part of the paper, we first discuss some fundamental issues of K. E. including the characteristic of K.E. as well as the definition of the term Kansei itself. In the 2nd part of the paper, the issue of human internal information such as emotions which reside the inside of human body, and hence, are unmeasurable from the outside are discussed as a basic problem lying over both B. M. and K.E. In particular, problems how to acquire human internal information are discussed through several examples.
Low expression of human β-defensin 1 in duodenum of celiac patients is partially restored by a gluten-free diet

Abstract Background: Human β-defensins (hBDs) are small cationic, widely expressed proteins involved in innate immunity that exert strong bactericidal activity toward various pathogens. However, the role of hBDs in various diseases to which bacterial infection add severity, as it is in celiac disease (CD), is not yet clear. We analyzed the expression of the hBD1, hBD2, hBD3 and hBD4 genes in patients with CD during the active phase and after remission following a gluten-free diet to determine their role in development and relapse of CD. Methods: We studied 21 unrelated adults with CD (confirmed by anti-thyroglobulin antibodies and intestinal biopsy); 14 were evaluated at diagnosis, before diet modification, and seven after 2 years of a gluten-free diet. Thirty-six unrelated adults served as controls. We analyzed the mRNA expression of hBD1, 2, 3 and 4 on biopsy samples of duodenum obtained from all patients during endoscopy for diagnostic purposes. We used real-time polymerase chain reaction with TaqMan probes and obtained gene expression data using the delta-Ct method. Results: hBD1 mRNA was significantly lower in patients with active CD compared with patients on diet modification, whereas the mRNA levels of the other three defensins did not differ significantly between the two subgroups. Interestingly, the gluten-free diet restored only partially hBD1 expression as compared to a normal group of celiac-free subjects. Conclusions: Our data reinforce the evidence that hBD1 expression is greatly reduced in the duodenum of patients with active CD. It also strengthens the concept that reduced activity of immune peptides may predispose individuals to bacterial proliferation that contributes to the pathogenesis of CD. Clin Chem Lab Med 2010;48:489–92.