Miracle-dz/UniFAR-FTUs huggingface dataset:
The effects of sulodexide on both clinical and molecular parameters in patients with mixed arterial and venous ulcers of lower limbs

Background Mixed venous and arterial ulcers account for approximately 15%–30% of all venous leg ulcerations. Several studies have shown that matrix metalloproteinases (MMPs) and neutrophil gelatinase-associated lipocalin (NGAL) play a central role in the pathophysiology of venous and arterial diseases. Some studies have shown the efficacy of glycosaminoglycans, such as sulodexide (SDX), in treating patients with leg ulcers. The aim of this study was to evaluate clinical effects of SDX and its correlation with MMPs and NGAL expression in patients with mixed arterial and venous leg ulcers. Methods Patients eligible for this study were of both sexes, older than 20 years, and with a clinical and instrumental diagnosis of mixed ulcer. Results Fifty-three patients of both sexes were enrolled and divided into two groups by means of randomization tables. Group A (treated group) comprised 18 females and ten males (median age: 68.7 years) treated with standard treatment (compression therapy and surgery) + SDX (600 lipoprotein lipase-releasing units/day intramuscularly) for 15 days followed by SDX 250 lipase-releasing units every 12 hours day orally for 6 months as adjunctive treatment. Group B (control group) comprised 17 females and eight males (median age: 64.2 years) treated with standard treatment only (compression therapy and surgery). The type of surgery was chosen according to anatomical level of vein incompetence: superficial venous open surgery and/or subfascial endoscopic perforating surgery. In all enrolled patients, blood samples were collected in order to evaluate the plasma levels of MMPs and NGAL through enzyme-linked immunosorbent assay. These results were compared to another control group (Group C) of healthy individuals. Moreover, biopsies of ulcers were taken to evaluate the tissue expression of MMPs and NGAL through Western blot analysis. Our results revealed that SDX treatment is able to reduce both plasma levels and tissue expression of MMPs improving the clinical conditions in patients with mixed ulcers. Conclusion Inhibition of MMPs could represent a possible therapeutic intervention to limit the progression of leg ulceration. In particular, our findings demonstrate the efficacy of SDX in patients with mixed arterial and venous chronic ulcers of the lower limbs.
Results of the Health Assessment Questionnaire for Japanese patients with systemic sclerosis--measuring functional impairment in systemic sclerosis versus other connective tissue diseases.

OBJECTIVE To evaluate the physical functional impairment in patients with systemic sclerosis (SSc) using the Health Assessment Questionnaire (HAQ) and to estimate the correlation of HAQ scores with the severity of SSc. METHODS One hundred and twenty-four outpatients with connective tissue disease, including 50 patients with SSc, were evaluated using the HAQ. Twelve patients were classified as having diffuse cutaneous SSc (dSSc) and 38 limited cutaneous SSc (lSSc). The severity classification and the guidelines for treatment (2004) were applied to Japanese SSc patients in order to evaluate the relationship between HAQ scores and disease activity in patients with multiple organ involvement. RESULTS In dSSc the HAQ category scores for eating, walking, grip, activity and the HAQ-disability index (HAQ-DI) showed the greatest deficits in all disease groups. The severity of disease activity correlated significantly with the scores for walking, reach, and the HAQ-DI. The severity of joint, heart, and pulmonary hypertension were correlated independently with the HAQ-DI score by multiple linear regression analysis. CONCLUSION Patients with dSSc suffer greater functional impairment than patients with other connective tissue diseases, and improvements in hand use and walking represent very important targets for both drug development and rehabilitation. As improvement in organ involvement (joints, heart as well as pulmonary hypertension) can lead to reduced functional impairment, they constitute an important target for therapy in SSc.
Multiple Streptococcus pneumoniae Serotypes in Aural Discharge Samples from Children with Acute Otitis Media with Spontaneous Otorrhea

ABSTRACT Among 55 children with cultures positive for acute otitis media with spontaneous otorrhea, 28 (51%) had cultures positive for aural Streptococcus pneumoniae, and in 10 of these, two distinct strains were detected, in which 5 had pairs of strains that were both capsule-bearing serotypes. Such cases were more likely to have cultures positive for other otopathogens than those with only one pneumococcus present.
Emergence of DNA Polymerase ε Antimutators That Escape Error-Induced Extinction in Yeast

DNA polymerases (Pols) ε and δ perform the bulk of yeast leading- and lagging-strand DNA synthesis. Both Pols possess intrinsic proofreading exonucleases that edit errors during polymerization. Rare errors that elude proofreading are extended into duplex DNA and excised by the mismatch repair (MMR) system. Strains that lack Pol proofreading or MMR exhibit a 10- to 100-fold increase in spontaneous mutation rate (mutator phenotype), and inactivation of both Pol δ proofreading (pol3-01) and MMR is lethal due to replication error-induced extinction (EEX). It is unclear whether a similar synthetic lethal relationship exists between defects in Pol ε proofreading (pol2-4) and MMR. Using a plasmid-shuffling strategy in haploid Saccharomyces cerevisiae, we observed synthetic lethality of pol2-4 with alleles that completely abrogate MMR (msh2Δ, mlh1Δ, msh3Δ msh6Δ, or pms1Δ mlh3Δ) but not with partial MMR loss (msh3Δ, msh6Δ, pms1Δ, or mlh3Δ), indicating that high levels of unrepaired Pol ε errors drive extinction. However, variants that escape this error-induced extinction (eex mutants) frequently emerged. Five percent of pol2-4 msh2Δ eex mutants encoded second-site changes in Pol ε that reduced the pol2-4 mutator phenotype between 3- and 23-fold. The remaining eex alleles were extragenic to pol2-4. The locations of antimutator amino-acid changes in Pol ε and their effects on mutation spectra suggest multiple mechanisms of mutator suppression. Our data indicate that unrepaired leading- and lagging-strand polymerase errors drive extinction within a few cell divisions and suggest that there are polymerase-specific pathways of mutator suppression. The prevalence of suppressors extragenic to the Pol ε gene suggests that factors in addition to proofreading and MMR influence leading-strand DNA replication fidelity.
A Multicenter, Prospective, Randomized, Double-blind Study to Evaluate the Safety and Efficacy of Saroglitazar 2 and 4 mg Compared to Pioglitazone 45 mg in Diabetic Dyslipidemia (PRESS V)

Background: Dual PPARα/γ can improve both metabolic effects and minimized the side effects caused by either PPARα or PPARγ agonist. The PRESS V study was aimed to evaluate the safety, tolerability, and efficacy of saroglitazar 2 mg and 4 mg capsules (Lipaglyn™; Zydus Code: ZYH1) as compared to high dose pioglitazone in patients with diabetic dyslipidemia. Methods: In this 26-week double-blind, parallel arm, phase 3 study patients with hypertriglyceridemia with type 2 diabetes mellitus (BMI > 23 kg/m2; hypertriglyceridemia: TG > 200 to 400 mg/dL; glycosylated hemoglobin [HbA1c] >7 to 9%) were enrolled from 14 sites in India. After 2 weeks of lifestyle modification, 122 patients were randomized double-blind to 24-week treatment with the study drugs (saroglitazar 2 mg or 4 mg or pioglitazone 45 mg once daily) in a 1:1:1 ratio. The primary end point was change in plasma triglyceride level at week 24. The secondary end points were change in lipid profile and fasting plasma glucose at week 24. Patients who received study medication and had undergone at least 1 postbaseline efficacy evaluation were included in the efficacy analysis. All randomized patients who received at least a single dose were included for safety evaluation. Results: The efficacy analysis included 109 patients (n = 37 in saroglitazar 2 mg; n = 39 in saroglitazar 4 mg; n = 33 in pioglitazone). Saroglitazar 2 mg and 4 mg significantly reduced (P < .001) plasma triglyceride from baseline by 26.4% (absolute change ± SD: −78.2 ± 81.98 mg/dL) and 45% (absolute change ± SD −115.4 ± 68.11 mg/dL), respectively, as compared to pioglitazone -15.5% (absolute change ± SD: −33.3 ± 162.41 mg/dL) at week 24. Saroglitazar 4 mg treatment also demonstrated marked decrease in low-density lipoprotein (5%), very-low-density lipoprotein (45.5%), total cholesterol (7.7%), and apolipoprotein-B (10.9%). Saroglitazar treatment was generally safe and well tolerated. No serious adverse events were reported in saroglitazar treatment arm and no persistent change in laboratory parameters. Conclusions: Saroglitazar appeared to be an effective and safe therapeutic option for improving hypertriglyceridemia in patients with type 2 diabetes mellitus.
SsrA‐mediated tagging and proteolysis of LacI and its role in the regulation of lac operon

SsrA RNA of Escherichia coli, also known as 10Sa RNA or tmRNA, acts both as tRNA and mRNA when ribosomes are paused at the 3′ end of an mRNA lacking a stop codon. This process, referred to as trans‐translation, leads to the addition of a short peptide tag to the C‐terminus of the incomplete nascent polypeptide. The tagged polypeptide is then degraded by C‐terminal‐specific proteases. Here, we focused on endogenous targets for the SsrA system and on a potential regulatory role of SsrA RNA. First, we show that trans‐translation events occur frequently in normally growing E.coli cells. More specifically, we report that the lacI mRNA encoding Lac repressor (LacI) is a specific natural target for trans‐translation. The binding of LacI to the lac operators results in truncated lacI mRNAs that are, in turn, recognized by the SsrA system. The SsrA‐mediated tagging and proteolysis of LacI appears to play a role in cellular adaptation to lactose availability by supporting a rapid induction of lac operon expression.
Persistent High Serum Bicarbonate and the Risk of Heart Failure in Patients With Chronic Kidney Disease (CKD): A Report From the Chronic Renal Insufficiency Cohort (CRIC) Study

Background Serum bicarbonate varies over time in chronic kidney disease (CKD) patients, and this variability may portend poor cardiovascular outcomes. The aim of this study was to conduct a time‐updated longitudinal analysis to evaluate the association of serum bicarbonate with long‐term clinical outcomes: heart failure, atherosclerotic events, renal events (halving of estimated glomerular filtration rate [eGFR] or end‐stage renal disease), and mortality. Methods and Results Serum bicarbonate was measured annually, in 3586 participants with CKD, enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study. Marginal structural models were created to allow for integration of all available bicarbonate measurements and proper adjustment for time‐dependent confounding. During the 6 years follow‐up, 512 participants developed congestive heart failure (26/1000 person‐years) and 749 developed renal events (37/1000 person‐years). The risk of heart failure and death was significantly higher for participants who maintained serum bicarbonate >26 mmol/L for the entire duration of follow‐up (hazard ratio [HR] 1.66; 95% confidence interval [CI], 1.23 to 2.23, and HR 1.36, 95% CI 1.02 to 1.82, respectively) compared with participants who kept their bicarbonate 22 to 26 mmol/L, after adjusting for demographics, co‐morbidities, medications including diuretics, eGFR, and proteinuria. Participants who maintained serum bicarbonate <22 mmol/L had almost a 2‐fold increased risk of renal disease progression (HR 1.97; 95% CI, 1.50 to 2.57) compared with participants with bicarbonate 22 to 26 mmol/L. Conclusion In this large CKD cohort, persistent serum bicarbonate >26 mmol/L was associated with increased risk of heart failure events and mortality. Further studies are needed to determine the optimal range of serum bicarbonate in CKD to prevent adverse clinical outcomes.
Crystal Structures of Human SIRT3 Displaying Substrate-induced Conformational Changes

SIRT3 is a major mitochondrial NAD+-dependent protein deacetylase playing important roles in regulating mitochondrial metabolism and energy production and has been linked to the beneficial effects of exercise and caloric restriction. SIRT3 is emerging as a potential therapeutic target to treat metabolic and neurological diseases. We report the first sets of crystal structures of human SIRT3, an apo-structure with no substrate, a structure with a peptide containing acetyl lysine of its natural substrate acetyl-CoA synthetase 2, a reaction intermediate structure trapped by a thioacetyl peptide, and a structure with the dethioacetylated peptide bound. These structures provide insights into the conformational changes induced by the two substrates required for the reaction, the acetylated substrate peptide and NAD+. In addition, the binding study by isothermal titration calorimetry suggests that the acetylated peptide is the first substrate to bind to SIRT3, before NAD+. These structures and biophysical studies provide key insight into the structural and functional relationship of the SIRT3 deacetylation activity.
Differential Regulation of Membrane Type 1-Matrix Metalloproteinase Activity by ERK 1/2- and p38 MAPK-modulated Tissue Inhibitor of Metalloproteinases 2 Expression Controls Transforming Growth Factor-β1-induced Pericellular Collagenolysis*

Acquisition of matrix metalloproteinase-2 (MMP-2) activity is temporally associated with increased migration and invasiveness of cancer cells. ProMMP-2 activation requires multimolecular complex assembly involving proMMP-2, membrane type 1-MMP (MT1-MMP, MMP-14), and tissue inhibitor of metalloproteinases-2 (TIMP-2). Because transforming growth factor-β1 (TGF-β1) promotes tumor invasion in advanced squamous cell carcinomas, the role of TGF-β1 in the regulation of MMP activity in a cellular model of invasive oral squamous cell carcinoma was examined. Treatment of oral squamous cell carcinoma cells with TGF-β1 promoted MMP-dependent cell scattering and collagen invasion, increased expression of MMP-2 and MT1-MMP, and enhanced MMP-2 activation. TGF-β1 induced concomitant activation of ERK1/2 and p38 MAPK, and kinase inhibition studies revealed a negative regulatory role for ERK1/2 in modulating acquisition of MMP-2 activity. Thus, a reciprocal effect on proMMP-2 activation was observed whereupon blocking ERK1/2 phosphorylation promoted proMMP-2 activation and MT1-MMP activity, whereas inhibiting p38 MAPK activity decreased proteolytic potential. The cellular mechanism for the control of MT1-MMP catalytic activity involved concurrent reciprocal modulation of TIMP-2 expression by ERK1/2 and p38 MAPKs, such that inhibition of ERK1/2 phosphorylation decreased TIMP-2 production, and down-regulation of p38 MAPK activity enhanced TIMP-2 synthesis. Further, p38 MAPK inhibition promoted ERK1/2 phosphorylation, providing additional evidence for cross-talk between MAPK pathways. These observations demonstrate the complex reciprocal effects of ERK1/2 and p38 MAPK in the regulation of MMP activity, which could complicate the use of MAPK-specific inhibitors as therapeutic agents to down-regulate the biologic effects of TGF-β1 on pericellular collagen degradation and tumor invasion.
Supporting soft real-time tasks in the xen hypervisor

Virtualization technology enables server consolidation and has given an impetus to low-cost green data centers. However, current hypervisors do not provide adequate support for real-time applications, and this has limited the adoption of virtualization in some domains. Soft real-time applications, such as media-based ones, are impeded by components of virtualization including low-performance virtualization I/O, increased scheduling latency, and shared-cache contention. The virtual machine scheduler is central to all these issues. The goal in this paper is to adapt the virtual machine scheduler to be more soft-real-time friendly. We improve two aspects of the VMM scheduler -- managing scheduling latency as a first-class resource and managing shared caches. We use enterprise IP telephony as an illustrative soft real-time workload and design a scheduler S that incorporates the knowledge of soft real-time applications in all aspects of the scheduler to support responsiveness. For this we first define a laxity value that can be interpreted as the target scheduling latency that the workload desires. The load balancer is also designed to minimize the latency for real-time tasks. For cache management, we take cache-affinity into account for real time tasks and load-balance accordingly to prevent cache thrashing. We measured cache misses and demonstrated that cache management is essential for soft real time tasks. Although our scheduler S employs a different design philosophy, interestingly enough it can be implemented with simple modifications to the Xen hypervisor's credit scheduler. Our experiments demonstrate that the Xen scheduler with our modifications can support soft real-time guests well, without penalizing non-real-time domains.
Did household consumption become more volatile

We show that volatility of household consumption, after accounting for predictable variation arising from movements in real interest rates, preferences and income shocks, increased between 1970 and 2002. For single parent households, and households headed by nonwhite or poorly educated individuals, this rise was significantly larger. This stands in sharp contrast with the dramatic fall in aggregate volatility of the US economy, and may have significant welfare implications. A spectacular fall in average covariances of consumption growth rates across households over this period accounts for the diverging paths of aggregate and household level volatilities.
Application of Binary Particle Swarm Optimization in Automatic Classification of Wood Species using Gray Level Co-Occurence Matrix and K-Nearest Neighbor

A bstract— This paper proposed an application of Binary Particle Swarm Optimization in automatic classification of wood species. The images of wood species are taken from Universiti Teknologi Malaysia’s CAIRO Wood Database which consists of 25 species. The features of the images are extracted using Gray Level Co-Occurrence Matrix. Then, Binary Particle Swarm Optimization is use to optimize feature selection and parameters related to it. The result indicates that the proposed approach obtained a better result compared to previous literatures with fewer features used as input for the classifier.
Evolution of a Novel Antiviral Immune-Signaling Interaction by Partial-Gene Duplication

The RIG-like receptors (RLRs) are related proteins that identify viral RNA in the cytoplasm and activate cellular immune responses, primarily through direct protein-protein interactions with the signal transducer, IPS1. Although it has been well established that the RLRs, RIG-I and MDA5, activate IPS1 through binding between the twin caspase activation and recruitment domains (CARDs) on the RLR and a homologous CARD on IPS1, it is less clear which specific RLR CARD(s) are required for this interaction, and almost nothing is known about how the RLR-IPS1 interaction evolved. In contrast to what has been observed in the presence of immune-modulating K63-linked polyubiquitin, here we show that—in the absence of ubiquitin—it is the first CARD domain of human RIG-I and MDA5 (CARD1) that binds directly to IPS1 CARD, and not the second (CARD2). Although the RLRs originated in the earliest animals, both the IPS1 gene and the twin-CARD domain architecture of RIG-I and MDA5 arose much later in the deuterostome lineage, probably through a series of tandem partial-gene duplication events facilitated by tight clustering of RLRs and IPS1 in the ancestral deuterostome genome. Functional differentiation of RIG-I CARD1 and CARD2 appears to have occurred early during this proliferation of RLR and related CARDs, potentially driven by adaptive coevolution between RIG-I CARD domains and IPS1 CARD. However, functional differentiation of MDA5 CARD1 and CARD2 occurred later. These results fit a general model in which duplications of protein-protein interaction domains into novel gene contexts could facilitate the expansion of signaling networks and suggest a potentially important role for functionally-linked gene clusters in generating novel immune-signaling pathways.
Learning in the presence of malicious errors

In this paper an extension of the distribution-free model of learning introduced by Valiant [Comm. ACM, 27(1984), pp. 1134–1142] that allows the presence of malicious errors in the examples given to a learning algorithm is studied. Such errors are generated by an adversary with unbounded computational power and access to the entire history of the learning algorithm’s computation. Thus, a worst-case model of errors is studied.The results of this research include general methods for bounding the rate of error tolerable by any learning algorithm, efficient algorithms tolerating nontrivial rates of malicious errors, and equivalences between problems of learning with errors and standard combinatorial optimization problems.
UV-B Irradiation Changes Specifically the Secondary Metabolite Profile in Broccoli Sprouts: Induced Signaling Overlaps with Defense Response to Biotic Stressors

Only a few environmental factors have such a pronounced effect on plant growth and development as ultraviolet light (UV). Concerns have arisen due to increased UV-B radiation reaching the Earth’s surface as a result of stratospheric ozone depletion. Ecologically relevant low to moderate UV-B doses (0.3–1 kJ m–2 d–1) were applied to sprouts of the important vegetable crop Brassica oleracea var. italica (broccoli), and eco-physiological responses such as accumulation of non-volatile secondary metabolites were related to transcriptional responses with Agilent One-Color Gene Expression Microarray analysis using the 2×204 k format Brassica microarray. UV-B radiation effects have usually been linked to increases in phenolic compounds. As expected, the flavonoids kaempferol and quercetin accumulated in broccoli sprouts (the aerial part of the seedlings) 24 h after UV-B treatment. A new finding is the specific UV-B-mediated induction of glucosinolates (GS), especially of 4-methylsulfinylbutyl GS and 4-methoxy-indol-3-ylmethyl GS, while carotenoids and Chl levels remained unaffected. Accumulation of defensive GS metabolites was accompanied by increased expression of genes associated with salicylate and jasmonic acid signaling defense pathways and up-regulation of genes responsive to fungal and bacterial pathogens. Concomitantly, plant pre-exposure to moderate UV-B doses had negative effects on the performance of the caterpillar Pieris brassicae (L.) and on the population growth of the aphid Myzus persicae (Sulzer). Moreover, insect-specific induction of GS in broccoli sprouts was affected by UV-B pre-treatment.
A control framework for snake robot locomotion based on shape control points interconnected by Bézier curves

This paper presents a control framework for shape control of snake robots for the purpose of locomotion. An advantage of the framework is that it allows the macroscopic shape of a snake robot to be controlled explicitly and intuitively. The framework is based on specifying the desired shape of the snake robot as a continuous shape curve defined by a set of shape control points interconnected by Bézier curves. We propose a novel approach for motion generation in which the shape curve is repeatedly extended according to a desired gait pattern while a virtual snake robot is progressed along the shape curve to retrieve joint reference angles for the physical snake robot. Practical applications of the proposed control framework are exemplified along with simulation results.