Miracle-dz/UniFAR-FTUs huggingface dataset:
Value and goals of treat-to-target in systemic lupus erythematosus: knowledge and foresight

Treat-to-target is a therapeutic strategy aimed at improving disease outcome through the achievement of shared treatment goals, which has dramatically ameliorated the prognosis of widespread disorders, such as hypertension or diabetes. Conversely, efforts to delineate treat-to-target in systemic lupus erythematosus (SLE) have failed in pinpointing common goals and treatment strategies, probably because of disease heterogeneity and lack of measurable biomarkers predicting disease course and ensuring a safe treatment tapering during quiescence. Given the detrimental effects of persistent disease activity and protracted corticosteroid therapy on patients’ outcome in lupus, disease remission should be pursued whenever possible. Fortunately, clinical remission is currently realistic for a greater number of patients than it was in the past, yet tight monitoring is required in order for patients to benefit from disease- and corticosteroid-free intervals, while minimizing the risk of disease flares. In everyday practice, patients should be brought to the lowest level of disease activity ensuring a significant benefit over a persistently active disease, being either clinical remission or low disease activity.
Novel MMP-9 Substrates in Cancer Cells Revealed by a Label-free Quantitative Proteomics Approach*S

Matrix metalloproteinase-9 (MMP-9) is implicated in tumor metastasis as well as a variety of inflammatory and pathological processes. Although many substrates for MMP-9, including components of the extracellular matrix, soluble mediators such as chemokines, and cell surface molecules have been identified, we undertook a more comprehensive proteomics-based approach to identify new substrates to further understand how MMP-9 might contribute to tumor metastasis. Previous proteomics approaches to identify protease substrates have depended upon differential labeling of each sample. Instead we used a label-free quantitative proteomics approach based on ultraperformance LC-ESI-high/low collision energy MS. Conditioned medium from a human metastatic prostate cancer cell line, PC-3ML, in which MMP-9 had been down-regulated by RNA interference was compared with that from the parental cells. From more than 200 proteins identified, 69 showed significant alteration in levels after depletion of the protease (>±2-fold), suggesting that they might be candidate substrates. Levels of six of these (amyloid-β precursor protein, collagen VI, leukemia inhibitory factor, neuropilin-1, prostate cancer cell-derived growth factor (PCDGF), and protease nexin-1 (PN-1)) were tested in the conditioned media by immunoblotting. There was a strong correlation between results by ultraperformance LC-ESI-high/low collision energy MS and by immunoblotting giving credence to the label-free approach. Further information about MMP-9 cleavage was obtained by comparison of the peptide coverage of collagen VI in the presence and absence of MMP-9 showing increased sensitivity of the C- and N-terminal globular regions over the helical regions. Susceptibility of PN-1 and leukemia inhibitory factor to MMP-9 degradation was confirmed by in vitro incubation of the recombinant proteins with recombinant MMP-9. The MMP-9 cleavage sites in PN-1 were sequenced. This study provides a new label-free method for degradomics cell-based screening leading to the identification of a series of proteins whose levels are affected by MMP-9, some of which are clearly direct substrates for MMP-9 and become candidates for involvement in metastasis.
External finger forces in submaximal five-finger static pinch prehension.

Small conductive polymer force sensors were attached to the distal phalangeal pads for measuring individual finger forces exerted during submaximal static pinch. A linear force summing strain gauge dynamometer for measuring resultant five-finger pinch force was grasped vertically using a neutral wrist posture. Individual finger forces were measured at fixed total pinch force levels of 10%, 20%, and 30% of maximum voluntary exertion using pinch spans of 45 mm and 65 mm. Total pinch force and individual finger forces were also measured while similarly grasping the dynamometer and supporting fixed weights for 1.0 kg, 1.5 kg, and 2.0 kg loads using pinch spans of 45 mm and 65 mm. The index and middle fingers exerted more than 3 N greater average force than the ring and small fingers for the fixed total pinch force task. No significant individual finger force differences were observed at the 10% maximum voluntary exertion level, however both the index and middle fingers exerted more than 5 N greater force than the ring and small fingers at the 30% maximum voluntary exertion level. The average contribution of the index, middle, ring, and small fingers were 33%, 33%, 17%, and 15%, respectfully, for the fixed total pinch force task. As exertion level increased from 10% to 30%, the contribution of the middle finger was not constant increasing from 25% to 38%. Total pinch force increased from 15 N to 30 N when the load weight increased from 1.0 kg to 2.0 kg. (ABSTRACT TRUNCATED AT 250 WORDS)
Rifaximin improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy.

BACKGROUND & AIMS Patients with cirrhosis and minimal hepatic encephalopathy (MHE) have driving difficulties but the effects of therapy on driving performance is unclear. We evaluated whether performance on a driving simulator improves in patients with MHE after treatment with rifaximin. METHODS Patients with MHE who were current drivers were randomly assigned to placebo or rifaximin groups and followed up for 8 weeks (n = 42). Patients underwent driving simulation (driving and navigation tasks) at the start (baseline) and end of the study. We evaluated patients' cognitive abilities, quality of life (using the Sickness Impact Profile), serum levels of ammonia, levels of inflammatory cytokines, and model for end-stage-liver disease scores. The primary outcome was the percentage of patients who improved in driving performance, calculated as follows: total driving errors = speeding + illegal turns + collisions. RESULTS Over the 8-week study period, patients given rifaximin made significantly greater improvements than those given placebo in avoiding total driving errors (76% vs 31%; P = .013), speeding (81% vs 33%; P = .005), and illegal turns (62% vs 19%; P = .01). Of patients given rifaximin, 91% improved their cognitive performance, compared with 61% of patients given placebo (P = .01); they also made improvements in the psychosocial dimension of the Sickness Impact Profile compared with the placebo group (P = .04). Adherence to the assigned drug averaged 92%. Neither group had changes in ammonia levels or model for end-stage-liver disease scores, but patients in the rifaximin group had increased levels of the anti-inflammatory cytokine interleukin-10. CONCLUSIONS Patients with MHE significantly improve driving simulator performance after treatment with rifaximin, compared with placebo.
EVIDENCE FAVORING THE ROLE OF THE GUT AS A CYTOKINE‐GENERATING ORGAN IN RATS SUBJECTED TO HEMORRHAGIC SHOCK

There is increasing evidence of an association between intestinal injury and the development of a septic state and distant organ failure. Since this phenomenon can occur in the absence of detectable systemic bacterial translocation (BT), we tested the hypothesis that shock-induced intestinal injury will result in the gut becoming a cytokine-generating organ by measuring interleukin 6 (IL-6) and tumor necrosis factor (TNF) levels in the portal blood, cardiac blood, and intestinal lymph of rats subjected to sham, 30, 60, or 90 min of hemorrhagic shock (30 mm Hg). These blood and lymph samples, as well as the mesenteric lymph nodes (MLN), spleens, and livers, were cultured for translocating bacteria. Although all the portal and cardiac blood samples were sterile, the portal blood levels of TNF and IL-6 were increased to a greater extent than simultaneously obtained cardiac blood samples in rats subjected to 60 or 90 min of shock (p < .05). The lymph IL-6 levels increased but were similar between the groups. BT was limited to the MLN and occurred in a dose-dependent fashion with 38, 63, and 100% of the animals having culture-positive MLNs after 30, 60, or 90 min of shock, respectively. In conclusion, after hemorrhagic shock, the gut appears to become a cytokine liberating organ even in the absence of detectable bacteria in the portal circulation.
An Update on Human Thyroid Hormone Receptors in Health and Disease: Chemistry, Physiology and Pathophysiology

Iodothyronines, the tetra- and tri-iodothyronines (T 4 and T 3 ), commonly known as thyroid hormones (THs), are secreted by thyroid glands. Thyroid hormones influence the growth and differentiation of every organ of the body via specific nuclear receptors (TRs), which belong to the nuclear receptor superfamily. Though thyroid glands secrete predominantly T 4 (which remains bound to its serum binding proteins), T 3 is the biologically active TH. Free T 4 enters the target cells through specific transporters and is converted into T 3 by cell-specific isoforms of cytoplasmic 5' deiodinase, which regulate the circulating T 3 levels and its availability for nuclear TRs in a tissue-specific manner. T 3 is then translocated to the nucleus, with the help of NADPH-dependent cytosolic transporter, where it binds to the monomers of TR subtypes (TRα and TRβ). Prior to the binding of T 3 , TR monomer dimerizes with the 9-cis retinoic acid or retinoid X receptor (RXR) and the TR-RXR heterodimer, in association with corepressors, binds to specific TR response element (TRE) in the target genes. Upon T 3 binding to the TR monomer of the TR-RXR-TRE complex, corepressors get released paving way for the binding of coactivators, thereby inducing the transcription of T 3 -responsive genes. Apart from the canonical nuclear signalling mechanism, membrane-mediated signalling by THs occurs through its interaction with plasma membrane integrin ανβ3. The impact of TH status and TR signalling on a broad range of genes makes studying its effect in vivo a difficult task. Studies on knock-in/out/mutant animal models and humans harboring several mutations of TR isoforms have helped explain various disorders of TH action, particularly the hypothyroid condition associated with the resistance to TH action. The aim of this review is to provide the readers with the information on THs biosynthesis along with the recent progress in TR signalling and its physiological impact on human health.
A multiple activation anti-windup design for systems with input saturation and dead-zone: Experiments on a satellite receiver

Input saturation and dead-zone phenomena are ubiquitous for the actuators in modern industries and military applications. However, in most of the existing literature, only the influence of the input saturation is considered. In order to overcome the adverse effects of the dead-zone as well as the input saturation, a multiple activation anti-windup approach that consists of immediate, anticipatory and delayed activations is proposed in this paper. These three types of compensators are designed in a cascade fashion. By using the adaptive simulated annealing (ASA for short) algorithms, we only need to give a series of the input and output datum. The compensation coefficients can be determined directly. A satellite communication on-the-move (satellite receiver for short) tracking experiment shows that the proposed multiple activation anti-windup approach significantly improves the performance of systems with input saturation and dead-zone.
Comparison of different Kalman filter approaches in deriving time varying connectivity from EEG data

Kalman filter approaches are widely applied to derive time varying effective connectivity from electroencephalographic (EEG) data. For multi-trial data, a classical Kalman filter (CKF) designed for the estimation of single trial data, can be implemented by trial-averaging the data or by averaging single trial estimates. A general linear Kalman filter (GLKF) provides an extension for multi-trial data. In this work, we studied the performance of the different Kalman filtering approaches for different values of signal-to-noise ratio (SNR), number of trials and number of EEG channels. We used a simulated model from which we calculated scalp recordings. From these recordings, we estimated cortical sources. Multivariate autoregressive model parameters and partial directed coherence was calculated for these estimated sources and compared with the ground-truth. The results showed an overall superior performance of GLKF except for low levels of SNR and number of trials.
Postoperative Hypoxemia in Morbidly Obese Patients With and Without Obstructive Sleep Apnea Undergoing Laparoscopic Bariatric Surgery

INTRODUCTION: The increased incidence of morbid obesity has resulted in an increase of bariatric surgical procedures. Obstructive sleep apnea (OSA) is a commonly encountered comorbidity in morbidly obese patients. Sedatives, analgesics, and anesthetics alter airway tone, and airway obstruction and death have been reported in patients with OSA after minimal doses of sedatives and anesthetics, yet there is a lack of consensus regarding the care of these patients. In this study, we sought to determine whether obese patients with polysomnography-confirmed diagnosis of OSA were at significantly greater risk for postoperative hypoxemic episodes in the first 24 h after laparoscopic bariatric surgery than morbidly obese patients without a diagnosis of OSA. METHODS: Adult subjects (Body Mass Index, 35–75 kg/m2) scheduled to undergo laparoscopic bariatric surgery were studied. A finger pulse oximetry probe was placed preoperatively and oxygen saturation (Spo2) was recorded continuously. All subjects underwent preoperative polysomnography testing within 4 wk of surgery. Anesthetic management was standardized, using propofol for induction and desflurane and remifentanil for maintenance of anesthesia. Patient-controlled analgesia programmed to deliver morphine, 1 mg. every 10 minutes, was used for pain management postoperatively. Hypoxemic episodes were scored as Spo2 >4% below the polysomnography study baseline and lasting for more than 10 s. RESULTS: Eight men and 32 women were enrolled and 1 subject had incomplete data. Thirty-one of the 40 subjects had polysomnography-confirmed OSA. Eight subjects used home continuous positive airway pressure devices nightly, and six of these used their device postoperatively. Preoperatively, subjects with OSA had lower nadir Spo2 during the polysomnography study and a larger number had an apnea/hypopnea index >10 episodes per hour compared with the non-OSA group. In the first 24 h postoperatively, there was no difference in the median Spo2 with and without oxygen therapy, between OSA and non-OSA groups.The number of episodes of oxygen desaturation >4% below the polysomnography study baseline value and the mean number of desaturation episodes per hour did not differ between the groups. CONCLUSIONS: In morbidly obese subjects, in the first 24 h after laparoscopic bariatric surgery, OSA does not seem to increase the risk of postoperative hypoxemia. Our data confirm that morbidly obese subjects, with or without OSA, experience frequent oxygen desaturation episodes postoperatively, despite supplemental oxygen therapy suggesting that perioperative management strategies in morbidly obese patients undergoing laparoscopic bariatric surgery should include measures to prevent postoperative hypoxemia.
Calcium/calmodulin‐dependent protein kinase type IV (CaMKIV) inhibits apoptosis induced by potassium deprivation in cerebellar granule neurons

The neuroprotective mechanisms of the Ca2+/calmodulin kinase (CaMK) signaling pathway were studied in primary cerebellar neurons in vitro. When switched from depolarizing culture conditions HK (extracellular K+ 30 mM) to LK (K+ 5 mM), these neurons rapidly undergo nuclear fragmentation, a typical feature of apoptosis. We present evidence that blockade of L‐type Ca2+ channels (nifedipine sensitive) but not N/P/Q‐type Ca2+ channels (omega‐conotoxin MVIIC sensitive) triggered apoptosis and CPP32/ caspase‐3‐like activity. The entry into apoptosis was associated with a progressive caspase‐3‐dependent cleavage of CaMKIV, but not of CaMKII. CaMKIV function in neuronal apoptosis was further investigated by overexpression of CaMKIV mutants by gene transfer. A dominant‐active CaMKIV mutant inhibited LK‐induced apoptosis whereas a dominant‐negative form induced apoptosis in HK, suggesting that CaMKIV exerts neuroprotective effects. The transcription factor CREB is a well‐described nuclear target of CaMKIV in neurons. When switched to LK, the level of phosphorylation of CREB, after an initial drop, further declined progressively with kinetics comparable to those of CaMKIV degradation. This decrease was abolished by caspase‐3 inhibitor. These data are compatible with a model where Ca2+ influx via L‐type Ca2+ channels prevents caspase‐dependent cleavage of CaMKIV and promotes neuronal survival by maintaining a constitutive level of CaMKIV/CREB‐dependent gene expression. —Sée, V. , Boutillier, A. ‐L. , Bito, H. , Loeffler, J.‐P. Calcium/calmodulin‐dependent protein kinase type IV (CaMKIV) inhibits apoptosis induced by potassium deprivation in cerebellar granule neurons. FASEB J. 15, 134–144 (2001)
Decreased sensitivity to vasoconstrictors in aortic rings after acute exposure to nitric oxide.

Nitric oxide (NO) has been postulated as a regulator of vascular reactivity, and the current study tested the hypothesis that NO-induced decreased sensitivity to vasoconstrictors persists following removal of NO. Endothelium-denuded segments of rat aorta were incubated 2-4 h at 37 degrees C with the NO donor S-nitroso-N-acetylpenicillamine (SNAP). Incubation produced rightward shifts in concentration response curves for phenylephrine [i.e., half-maximum effective concentration (EC50; in microM): control = 0.016, NO = 0.14], aluminum fluoride (i.e., EC50 in mM: control = 1.66, NO = 2.29), and KCl (i.e., EC50 in mM: control = 5.9, NO = 23.9). Similar shifts were seen for two other NO donors. The SNAP-induced shift was not attenuated by a guanylyl cyclase inhibitor, LY-83583 (10 microM) and was not mimicked by 8-bromoguanosine 3',5'-cyclic monophosphate (100 microM). It was attenuated by 1,4-naphthoquinone (50 microM), an inhibitor of endogenous mono-ADP ribosyltransferases. NO incubation increased cGMP content (4.6 +/- 0.8 vs. 1.5 +/- 0.15 pmol/mg protein), an increase unaffected by 1,4-naphthoquinone (3.3 +/- 1.0 pmol/mg protein) but prevented by LY-83583 (1.6 +/- 0.36 pmol/mg protein). ADP ribosylation of three proteins was observed in membranes from HEK 293 cells: 88,66, and 38 kDa. ADP ribosylation of the 38-kDa protein was stimulated in a concentration-dependent manner by NO but was not decreased by 1,4-naphthoquinone. In conclusion, NO produces a long-lasting inhibition of vascular contractility by both a cGMP-dependent and -independent mechanism. Based on the observations of 1,4-naphthoquinone, we conclude that the cGMP-independent mechanism is not stimulation of endogenous ADP ribosylation but some other covalent modification in the pathway that mediates contraction.
African American Students and No Child Left Behind Legislation: Progression or Digression in Educational Attainment

The No Child Left Behind (NCLB) federal legislation has dramatically changed the way schools and school districts measure educational attainment for all students. In this article, the researchers examine whether African Americans have progressed or digressed in their educational attainment five years after the implementation of NCLB. To provide a clear picture on the status of educational attainment for African American K? 12 public school students across the United States, an analysis of data from the National Assessment of Educational Progress (NAEP) was utilized. This analysis was grounded in the theory of structural inequality. Finally, recommendations to K? 12 educational practitioners along with education policy makers and funding agencies are discussed.
Comparison of Screening Procedures for Mycobacterium tuberculosis Infection Among Patients with Inflammatory Diseases

Objective. To test if Mycobacterium tuberculosis screening results differ among patients with inflammatory disease depending on whether the QuantiFeron TB-Gold test (QFT) or tuberculin skin test (TST) is used; and to evaluate if a possible difference is influenced by the presence of risk factors or immunosuppression. Methods. The interferon-γ response to in vitro stimulation of M. tuberculosis-specific antigens was measured with QFT and results were compared with TST. Associations to bacillus Calmette-Guerin (BCG) vaccination, risk factors, and immunosuppression were analyzed for both tests. Results. QFT and TST results were available for 294/302 and 241/302 patients, respectively; 234 had results from both tests. Twenty-one (7%) tested positive with QFT and 45 (19%) with TST. A positive QFT was associated with risk factors for M. tuberculosis infection: i.e., birth or upbringing in a TB-endemic area [risk ratio (RR) = 7.8, 95% CI 1.5–18.2, p < 0.001], previous TB treatment (RR 4.7, 95% CI 1.6–13.5, p = 0.005), and any latent TB infection risk factor (RR 4.7, 95% CI 2.1–11.0, p = 0.0002). Treatment with corticosteroids increased the risk for an inconclusive QFT result (RR 4.2, 95% CI 1.6–10.7, p = 0.04) and decreased the risk for a positive TST result (RR 0.4, 95% CI 0.1–1.0, p = 0.04). Agreement between the tests was low (kappa 0.2, 95% CI 0.02–0.3, p = 0.002). Conclusion. The study documented a high degree of discordant positive QFT and TST results. A positive QFT was more closely associated with risk factors for M. tuberculosis infection than the TST. The use of corticosteroids affected test outcome by increasing the risk for an inconclusive QFT result and decreasing the risk for a positive TST result.
Generation of an inverting herpes simplex virus 1 mutant lacking the L-S junction a sequences, an origin of DNA synthesis, and several genes including those specifying glycoprotein E and the alpha 47 gene

The herpes simplex virus genome consists of two components, L and S, that invert relative to each other to yield four isomeric arrangements, prototype (P), inversion of the S component (Is), inversion of the L component (Il), and inversion of both components (Isl). Previous studies have shown that the 500-base-pair a sequences flanking the two components contain a cis-acting site for inversion. In an attempt to insert a third copy of the alpha 4 gene, the major regulatory gene mapping in the repeats flanking the S component, a fragment containing the alpha 4 gene and an origin of DNA synthesis, was recombined into the thymidine kinase gene mapping in the unique sequences of the L component. The resulting recombinants showed massive rearrangements and deletions mapping in the S component and in the junction between the L and S components. One recombinant (R7023) yielded two isomeric DNA arrangements, a major component consisting of Is and a minor component consisting of Isl. In these arrangements, the genome lacked the gene specifying glycoprotein E and all contiguous genes located between it and the alpha 0 gene in the inverted repeats of the L component. Among the deleted sequences were those encoding an origin of viral DNA synthesis, the alpha 47 gene, and the a sequences located at the junction between the L and S-components. The recombinant grew well in rabbit skin, 143TK-, and Vero cell lines. We conclude that the four unique genes deleted in R7023 are not essential for the growth of herpes simplex virus, at least in the cell lines tested, and that the b sequence of the inverted repeats of the L component also contains cis-acting sites for the inversion of herpes simplex virus DNA sequences.