Miracle-dz/UniFAR-FTUs huggingface dataset:
Biochemical and Structural Assessment of the 1-N-Azasugar GalNAc-isofagomine as a Potent Family 20 β-N-Acetylhexosaminidase Inhibitor*

Azasugar inhibitors of the isofagomine class are potent competitive inhibitors of configuration-retaining β-glycosidases. This potency results from the formation of a strong electrostatic interaction between a protonated endocyclic nitrogen at the “anomeric” center of the inhibitor and the catalytic nucleophile of the enzyme. Although the majority of retaining β-glycosidases use a mechanism involving a carboxylate residue as a nucleophile, Streptomyces plicatusβ-N-acetylhexos-aminidase (SpHEX) and related family 20 glycosidases lack such a catalytic residue and use instead the carbonyl oxygen of the 2-acetamido group of the substrate as a nucleophile to “attack” the anomeric center. Thus, a strong electrostatic interaction between the inhibitor and enzyme is not expected to occur; nonetheless, the 1-N-azasugar (2R,3R,4S,5R)-2-acetamido-3,4-dihydroxy-5-hydroxymethyl-piperidinium hydrochloride (GalNAc-isofagomine·HCl), which was synthesized and assayed for its ability to inhibit SpHEX, was found to be a potent competitive inhibitor of the enzyme (K i = 2.7 μm). A crystallographic complex of GalNAc-isofagomine bound to SpHEX was solved and refined to 1.75 Å and revealed that the lack of a strong electrostatic interaction between the “anomeric” center of GalNAc-isofagomine andSpHEX is compensated for by a novel 2.8-Å hydrogen bond formed between the equatorial proton of the endocyclic nitrogen of the azasugar ring and the carboxylate of the general acid-base residue Glu-314 of SpHEX. This interaction appears to contribute to the unexpected potency of GalNAc-isofagomine towardSpHEX.
Modelling the effectiveness and risks of vaccination strategies to control classical swine fever epidemics

In a recent update of the Dutch contingency plan for controlling outbreaks of classical swine fever (CSF), emergency vaccination is preferred to large-scale pre-emptive culling. This policy change raised two questions: can emergency vaccination be as effective as pre-emptive culling, and what are the implications for showing freedom of infection? Here, we integrate quantitative information available on CSF virus transmission and vaccination effects into a stochastic mathematical model that describes the transmission dynamics at the level of animals, farms and livestock areas. This multilevel approach connects individual-level interventions to large-scale effects. Using this model, we compare the performance of five different control strategies applied to hypothetical CSF epidemics in The Netherlands and, for each of these strategies, we study the properties of three different screening scenarios to show freedom of infection. We find that vaccination in a ring of 2 km radius around a detected infection source is as effective as ring culling in a 1 km radius. Feasible screening scenarios, adapted to the use of emergency vaccination, can reduce the enhanced risks of (initially) undetected farm outbreaks by targeting vaccinated farms. Altogether, our results suggest that emergency vaccination against CSF can be equally effective and safe as pre-emptive culling.
Efficient frame selection schemes for multi-reference and variable block size Motion Estimation

Multi-reference and variable block size Motion Estimation (ME) can improve the coding efficiency, but it also requires a huge computational complexity. This paper introduces efficient frame selection schemes for the multi-reference and variable block size ME. The proposed modified frame selection scheme can reduce the number of search points about 18% compared with existing schemes. In addition, the proposed hierarchical frame selection scheme can efficiently support variable block size ME. Since the proposed frame selection schemes are separated from the block matching process, the proposed schemes can be used with any existing single reference fast search algorithms.
The Effect of Posthypnotic Suggestion, Hypnotic Suggestibility, and Goal Intentions on Adherence to Medical Instructions

Abstract The effects of implementation intentions and posthypnotic suggestion were investigated in 2 studies. In Experiment 1, participants with high levels of hypnotic suggestibility were instructed to take placebo pills as part of an investigation of how to best enhance compliance with medical instruction. In Experiment 2, participants with high, medium, and low levels of hypnotic suggestibility were asked to run in place, take their pulse rate before, and send an e-mail report to the experimenter each day. Experiment 1 revealed enhanced adherence as a function of both implementation intentions and posthypnotic suggestion. Experiment 2 failed to find any significant main effects but found a significant interaction between suggestibility and the effects of posthypnotic suggestion. Posthypnotic suggestion enhanced adherence among high suggestible participants but lowered it among low suggestibles.
Fluorescence Resonance Energy Transfer Reveals Interleukin (IL)-1-dependent Aggregation of IL-1 Type I Receptors That Correlates with Receptor Activation (*)

Fluorescence resonance energy transfer (FRET) was used to investigate whether interleukin-1 (IL-1) causes the aggregation of IL-1 type I receptors (IL-1 RI) at the cell surface. For these experiments, a noncompetitive anti-IL1 RI monoclonal antibody, M5, was labeled separately with a donor probe, fluorescein isothiocyanate, or with an acceptor carbocyanine probe, Cy3. Donor-labeled M5 and acceptor-labeled M5 were simultaneously bound to transfected mouse IL-1 RI on either C-127 mouse mammary carcinoma cells or on Chinese hamster ovary (CHO)-K1 cells, and the ratio of acceptor emission at 590 nm to donor emission at 525 nm (excitation at 488 and 514 nm) was monitored with flow cytometry as an indicator of FRET. Addition of a saturating concentration of human IL-1α at 22°C causes a time-dependent increase in FRET for both cell lines that indicates IL-1-dependent self-association of IL-1 RI. Binding of the IL-1 receptor antagonist at 22°C causes little or no FRET for both cell lines, indicating a correlation between receptor aggregation and the ability of the ligand to stimulate a functional response. When donor-labeled and acceptor-labeled Fab fragments of M5 are used to monitor FRET, IL-1α causes efficient energy transfer in the CHO-K1 cells at 22°C, but not at 4°C. In contrast, IL-1α causes much less FRET at 22°C in C-127 cells when the M5 Fab fragments are used instead of the intact bivalent M5. In a striking parallel, IL-1α-dependent activation of prostaglandin E2 production depends on the bivalent M5 antibody in the C-127 cells, but is independent of this monoclonal antibody in the CHO-K1 cells. These results provide a strong correlation between the ability of IL-1 to cause the aggregation of IL-1 RI and the stimulation of a functional response.
5-bit Folded Interpolated ADC in 90-nm CMOS Technology

High-speed, low-resolution power consumption of ADCs can be reduced from calibration. However, these solutions present some drawbacks such as calibration time, calibration algorithm complexity and die area increase. In alternative A 5-bit 1-Gs/s flash ADC is reported using a 180nm CMOS with folded interpolated technique without calibration that reduce the number of comparator by a factor of 4, A factor of two due to the folding architecture and another factor of two due to the interpolation technique. The ADC uses double tail dynamic comparator which operates with a fixed bias current and with reduced kickback noise, allowing increasing the input transistor sizes. This improves matching and avoiding calibration. Thus the results of computer simulation show that ADC achieves 1Gs/s sampling rate and 2.28mW power consumption (at 1.2v power supply). Reported DNL and INL are 0.9LSB respectively ,SNDR and SFDR are 28.24Db and 31.16Db respectively, ENOB(effective number of bits) is 4.4bit . ADC figure of merits 0.25Pj/conversion-step at 1Gs/s. KeywordsAnalog circuits, Flash ADC, Folded comparator, Preamplifier, Interpolation, mixed analog/digital signal.
Effect of short-term high-protein compared with normal-protein diets on renal hemodynamics and associated variables in healthy young men.

BACKGROUND High-protein diets are effective for weight reduction; however, little is known about the potential adverse renal effects of such diets. OBJECTIVE The aim of our study was to compare the effect of a high-protein (HP) with a normal-protein (NP) diet on renal hemodynamics and selected clinical-chemical factors. DESIGN We prospectively studied the effect of an HP diet (2.4 g x kg(-1) x d(-1)) with that of an NP diet (1.2 g x kg(-1) x d(-1)) on the glomerular filtration rate (assessed on the basis of sinistrin-an inulin analog-clearance) and renal plasma flow (para-aminohippuric acid clearance) by using the constant infusion technique. Filtration fraction and renal vascular resistance were calculated. Twenty-four healthy young men followed the 2 diet protocols for 7 d each in a crossover design. They were individually advised by a dietitian to achieve the planned protein intake by selecting normal foods under isocaloric conditions. Serum and urinary variables and renal hemodynamics were measured on day 7 of both diets. RESULTS The glomerular filtration rate (NP: 125 +/- 5 mL/min; HP: 141 +/- 8 mL/min; P < 0.001) and filtration fraction (NP: 23 +/- 5%; HP: 28 +/- 5%; P < 0.05) increased significantly with the HP diet. Renal plasma flow was not significantly different between the HP (496 +/- 25 mL/min) and NP (507 +/- 18 mL/min) phases. Renal vascular resistance was not significantly different between the NP (94 +/- 6 mm Hg x mL(-1) x min(-1)) and HP (99 +/- 8 mm Hg x mL(-1) x min(-1)) phases. Blood urea nitrogen, serum uric acid, glucagon, natriuresis, urinary albumin, and urea excretion increased significantly with the HP diet. CONCLUSIONS A short-term HP diet alters renal hemodynamics and renal excretion of uric acid, sodium, and albumin. More attention should be paid to the potential adverse renal effects of HP diets.
A Pooled Analysis of Two Randomized, Double‐Blind, Placebo‐Controlled Trials of Milnacipran Monotherapy in the Treatment of Fibromyalgia

Milnacipran has been shown to significantly improve the pain, global well‐being, and physical function of fibromyalgia (FM), and is approved by the U.S. Food and Drug Administration for the management of this disorder. Post hoc analyses of data from two pivotal trials were conducted to further assess the clinical benefits of milnacipran, to determine the impact of baseline pain severity on treatment outcomes, and to confirm the safety and tolerability of this medication in patients with FM. Patients in these trials were randomized to placebo (n = 624), milnacipran 100 mg/day (n = 623), or milnacipran 200 mg/day (n = 837). Two different composite responder analyses were used to evaluate efficacy: a 2‐measure analysis, requiring ≥ 30% improvement from baseline visual analog scale 24‐hour recall pain scores and a Patient Global Impression of Change (PGIC) score of “very much improved” or “much improved”; and a 3‐measure analysis, requiring a ≥ 6‐point improvement from baseline in SF‐36 Physical Component Summary scores in addition to the pain and PGIC criteria. Additionally, a pooled analysis of mean changes from baseline pain scores was conducted in order to evaluate the efficacy of milnacipran over the entire course of treatment. At 3 months, composite responder rates were significantly higher in the milnacipran treatment groups than in the placebo group (2‐ and 3‐measure composite responder analyses: P ≤ 0.001, both doses vs. placebo). These improvements were not dependent on baseline pain severity. Similar composite responder results were observed in patients who continued treatment for up to 6 months. Significant improvements in mean pain scores were seen with both doses of milnacipran vs. placebo as early as 1 week after treatment initiation and were sustained for up to 6 months of milnacipran treatment. The most common adverse events associated with milnacipran were nausea, headache, and constipation.
Preselection of recombinant gene integration sites enabling high transcription rates in CHO cells using alternate start codons and recombinase mediated cassette exchange

Site‐specific recombinase mediated cassette exchange (RMCE) enables the transfer of the gene of interest (GOI) into pre‐selected genomic locations with defined expression properties. For the generation of recombinant production cell lines, this has the advantage that screening for high transcription rates at the genome integration site would be required only once, with the possibility to reuse the selected site for new products. Here, we describe a strategy that aims at the selection of transcriptionally active genome integration sites in Chinese Hamster Ovary (CHO) cells by using alternate start codons in the surface reporter protein CD4, in combination with FACS sorting for high expressers. The alternate start codon reduces the translation initiation efficiency and allows sorting for CHO cells with the highest transcription rates, while RMCE enables the subsequent exchange of the CD4 against the GOI. We have shown that sorted cell pools with the CD4 reporter gene containing the alternate start codon CTG lead to higher GFP signals and higher antibody titers upon RMCE as compared to cell pools containing the ATG start codon of the CD4 reporter. Despite the absence of any subcloning step, the final cell pool contained the CD4 gene in a single genome integration site.
Some Dielectric and Mechanical Properties of Heat Treated Biaxially Drawn Pet Films

The dc dielectric strength of heat-treated biaxially drawn polyethylene terephthalate (PET) is studied under mechanical stresses. The sample is prepared on films with a draw ratio of 3.3x3. 9 obtained by a continuous process. To study the effect of crystallinity on the dielectric strength, the sample that is held to constant size is annealed for durations of 1 and 60 min in a silicone oil bath maintained at a fixed temperature within ±2°C. The annealing temperature range is from 100 to 2200C. The maximum dielectric strength of the sample under no mechanical stress is found to occur at an annealing temperature of about 1400C. But the compressive stress showing maximum dielectric strength under compressive stress increases with the annealing temperature, and its value is not significantly varied by the cooling process after annealing. Compared with undrawn and uniaxially drawn PET, the biaxially drawn sample has good mechanical properties and dielectric strength characteristics under mechanical stresses. However, it is believed that the best annealing condition should be decided by the requirements for the electrical and mechanical characters of the sample.
RAP80 Targets BRCA1 to Specific Ubiquitin Structures at DNA Damage Sites

Mutations affecting the BRCT domains of the breast cancer–associated tumor suppressor BRCA1 disrupt the recruitment of this protein to DNA double-strand breaks (DSBs). The molecular structures at DSBs recognized by BRCA1 are presently unknown. We report the interaction of the BRCA1 BRCT domain with RAP80, a ubiquitin-binding protein. RAP80 targets a complex containing the BRCA1-BARD1 (BRCA1-associated ring domain protein 1) E3 ligase and the deubiquitinating enzyme (DUB) BRCC36 to MDC1-γH2AX–dependent lysine6- and lysine63-linked ubiquitin polymers at DSBs. These events are required for cell cycle checkpoint and repair responses to ionizing radiation, implicating ubiquitin chain recognition and turnover in the BRCA1-mediated repair of DSBs.
Reference ranges for assessment of unilateral lymphedema in legs by bioelectrical impedance spectroscopy.

BACKGROUND Secondary unilateral lymphedema in the leg may occur as a consequence of pelvic surgery and/or radiation therapy, which causes damage to the pelvic lymphatic system. To date, assessment has been typically by manual measurement of the volume excess of the affected leg compared to the contralateral leg. In contrast, the assessment of unilateral arm lymphedema is readily accomplished by the use of bioelectrical impedance spectroscopy (BIS) as an increased inter-arm impedance ratio due to the presence of excess lymph in the affected arm relative to that of the unaffected arm. The presence of lymphedema is defined by a value of this ratio greater than the mean ratio plus three standard deviations (SD) observed in a comparable healthy population. The aim of the present study was to determine the equivalent reference range of the impedance ratio for the legs. This would allow a cut-off value to be established as a criterion for the detection and assessment of lower limb lymphedema. METHODS The impedances of the legs of 172 healthy females and 150 healthy males, measured by BIS, were extracted from an accumulated database of impedance data. These data were used to determine the normal distribution of inter-leg impedance ratios and the reference range and threshold value (mean + 3 SD). RESULTS The presence of lymphedema is indicated when the impedance ratio exceeds 1.167 in males and 1.136 in females. Unlike in the arms, the effect of limb dominance in the legs is minimal and it is suggested that no correction for limb dominance is warranted. CONCLUSIONS The impedance ratio thresholds for lymphedema of the legs have been established, opening the way for BIS to become established clinically for the early detection and assessment of lower limb lymphedema.
Pharmacokinetics of fentanyl as a possible explanation for recurrence of respiratory depression.

The pharmacokinetics of fentanyl are complicated by an additional increase in plasma concentration during the elimination phase of the drug. We have confirmed that fentanyl is excreted in the gastric juice and reabsorbed from the alkaline medium of the small intestine. In addition, the stomach wall in rats has an important storage capacity for fentanyl. A maximum of about 20% of the dose was found in the stomach wall after i.v. injection. In man the resected part of the stomach contained 16% of the dose, 10 min after injection. These observations could be important in explaining the occurrence of respiratory depression in the period after operation.
Sp1 coordinately regulates de novo lipogenesis and proliferation in cancer cells

Cancers express high levels of fatty acid synthase (FAS) from which they derive fatty acids for membrane biosynthesis to sustain cell proliferation. How cancer cells coordinate de novo lipogenesis and proliferation has not been investigated. Transcription factors Sp1, Sp3 and Sp4 are overexpressed in a variety of cancers and regulate gene expression by interacting with GC‐rich Sp1 binding sites. Genes encoding FAS and cell cycle proteins such as CDC25A contain Sp1 binding sites in their promoters. We demonstrate by RNA interference that Sp1, Sp3 and Sp4 all play a role in regulating CDC25A expression and proliferation in human breast cancer cells. Only Sp1, however, also regulates FAS. Furthermore, mithramycin, which blocks Sp1 binding sites, decreased proliferation, inhibited CDC25A and FAS expression and reduced binding of Sp1 to the promoters of these genes as assessed by ChIP assays. Conversely, 17β‐estradiol (E2) increased proliferation and CDC25A and FAS expression along with increased binding of Sp1 to the promoters of the 2 genes. In addition, we showed that the expression of sterol regulatory element‐binding protein‐1c (SREBP‐1c), the only transcription factor that has been shown to regulate genes of lipogenic enzymes in cancer cells, is also regulated by Sp1. Finally, we demonstrated that Sp1 plays a role in sustaining proliferation and FAS expression in colon as well as prostate cancer cells. Overall, these observations suggest that Sp1 coordinately regulates de novo lipogenesis and proliferation in cancer cells.
A force-reflecting teleoperated hand system for the study of tactile sensing in precision manipulation

The author describes a teleoperated hand system developed to study the role of tactile and fine-force sensing in telemanipulation. Both master and slave manipulators are two-fingered hands designed for precision tasks that humans typically execute with a pinch grasp. A direct drive parallel linkage configuration and brushless DC servomotors permit smooth, accurate control of contact forces and small motions, which is essential for effective tactile sensing and display. Initial experiments demonstrated that an operator can perform precision tasks using this system, and that the ability to convey small force levels to the operator required careful attention to the coupling between the operator's finger tips and the master manipulator. The system has been used to demonstrate that a tactile display can convey frictional information sensed at the slave manipulator. <<ETX>>
n-3 Polyunsaturated Fatty Acids Suppress the Localization and Activation of Signaling Proteins at the Immunological Synapse in Murine CD4+ T Cells by Affecting Lipid Raft Formation1

The molecular properties of immunosuppressive n-3 polyunsaturated fatty acids (PUFA) have not been fully elucidated. Using CD4+ T cells from wild-type control and fat-1 transgenic mice (enriched in n-3 PUFA), we show that membrane raft accumulation assessed by Laurdan (6-dodecanoyl-2-dimethyl aminonaphthalene) labeling was enhanced in fat-1 cells following immunological synapse (IS) formation by CD3-specific Ab expressing hybridoma cells. However, the localization of protein kinase Cθ, phospholipase Cγ-1, and F-actin into the IS was suppressed. In addition, both the phosphorylation status of phospholipase Cγ-1 at the IS and cell proliferation as assessed by CFSE labeling and [3H]thymidine incorporation were suppressed in fat-1 cells. These data imply that lipid rafts may be targets for the development of dietary agents for the treatment of autoimmune and chronic inflammatory diseases.
Maternal vitamin D receptor genetic variation contributes to infant birthweight among black mothers

Racial disparity in pregnancy outcomes is one of the most striking and poorly understood inequalities in American health. Genetic variability may be an important host factor influencing disparate birth outcomes between non‐Hispanic black (NHB) and non‐Hispanic white (NHW) women. Race‐specific allelic frequencies in the vitamin D receptor (VDR) gene suggest its potential as a gene involved in health disparities. The Healthy Pregnancy, Healthy Baby Study is a prospective cohort of pregnant women aimed at identifying genetic, social, and environmental contributors to disparities in pregnancy outcomes in Durham, NC. VDR haplotype tagging single nucleotide polymorphisms (SNPs) were genotyped via Taqman assays for 615 women. Analysis of variance was used to examine the association between maternal genotype and infant birthweight. Eight of 38 SNPs examined showed nominal significance among NHB women, with one VDR SNP (rs7975232) surpassing the multiple testing significance threshold. rs7975232, an anonymous polymorphism, is part of a VDR gene haplotype associated with variation in mRNA stability. mRNA stability can affect the amount of protein produced, thus directly affecting vitamin D levels and calcium homeostasis. In contrast to NHBs, there was no association between any VDR SNP and birthweight for NHWs. Genetic factors contributing to disparities in birth outcomes are not expected to be explained entirely by variation in a single gene. Nevertheless, our results suggest that maternal VDR gene polymorphisms do influence birthweight with differential effects accruing across racial groups. Further research identifying the functionality of VDR gene polymorphisms in pregnant women will improve our understanding of the underlying mechanisms influencing birthweight. © 2011 Wiley‐Liss, Inc.