Miracle-dz/UniFAR-FTUs huggingface dataset:
CYP2D6 polymorphism screening in a selected population of Spain (La Alpujarra): No effect of geographical isolation

Background: There is growing interest in theCYP2D6 gene because of its key role in the metabolism of numerous commonly used drugs. Aim: We compared the frequency of the most frequent nullCYP2D6 alleles (CYP2D6*3,CYP2D6*4,CYP2D6*5,CYP2D6*6,CYP2D6*7 andCYP2D6*8) between individuals from the Spanish population and from La Alpujarra. Subjects and methods: The present study comprises Spanish cohort (n = 185) and from La Alpujarra (n = 104). The latter is a small mountainous region of Spain that shows a remarkable degree of geographical and cultural isolation. We genotyped six polymorphisms in the coding region of theCYP2D6 gene, i.e. five single nucleotide polymorphisms (SNP) (CYP2D6*3,CYP2D6*4,CYP2D6*6,CYP2D6*7 andCYP2D6*8) and one deletion (CYP2D6*5). Results: No significant differences were observed between groups in allelic and genotype distributions of the aforementioned variants. The total frequency of functional alleles was comparable between the two groups (79% and 81.3% in controls and La Alpujarra, respectively). Conclusion: Despite demographic and cultural isolation in La Alpujarra, the distribution ofCYP2D6 polymorphisms in habitants of this area is similar to that reported in the rest of Spain. At present, there seems to be little allele heterogeneity inCYP2D6 amongst different European populations (e.g. amongst different Spanish populations) that have shown diversity in other loci.
An Open-Label, Randomized Comparative Pilot Study of a Single-Class Quadruple Therapy Regimen versus a 2–Class Triple Therapy Regimen for Individuals Initiating Antiretroviral Therapy

Objective To examine the antiviral potency and tolerability profile of a single-class four drug (quadruple) nucleoside reverse transcriptase inhibitor (NRTI) regimen compared with a 2-class standard-of-care regimen. Methodology A three-centre, randomized, open-label comparative pilot study of zidovudine/lamivudine/efavirenz (triple) versus abacavir/lamivudine/zidovudine/tenofovir (quadruple) therapy in HIV-1-infected, treatment-naive individuals. Both regimens were taken without regard to food and consisted of a twice-daily regimen and 3 pills/day. The study power was based on time-weighted average changes in HIV-1 RNA load. Results A total of 114 individuals (56 triple, 57 quadruple) received at least one dose of medication. Patients were well matched at baseline for viral load (mean 5.26 log10 versus 5.13 log10, respectively) and CD4 cell count (median 193 versus 153 cells/mm3, respectively). The two regimens performed similarly with regards to all endpoints. At week 48, by intention-to-treat, missing=failure analysis, 68% of triple- and 67% of quadruple-drug treated patients had an HIV-1 RNA <50 copies/ml (P>0.05). On-treatment analysis showed 40/40 (100%) of triple- and 39/40 (97.5%) of quadruple-drug treated patients (P=0.996) had responded to <50 copies/ml. No unexpected adverse events were reported. Changes in total cholesterol and triglycerides were modest but significantly favoured the quadruple therapy regimen at multiple time points. Conclusion This pilot study suggests a quadruple NRTI-based regimen provides similar antiviral potency, tolerability and administrative characteristics to a 2-class triple therapy regimen. These findings should be confirmed in a more fully powered study. Potent quadruple NRTI-based regimens may have advantages for some individuals with regards to salvageability, tolerability and drug interactions.
The Role of Internal Models in Motion Planning and Control: Evidence from Grip Force Adjustments during Movements of Hand-Held Loads

We investigated the issue of whether or not the CNS makes use of an internal model of the motor apparatus in planning and controlling arm movements. In particular, we tested the ability of subjects to predict different hand-held loads by examining grip force adjustments used to stabilize the load in the hand during arm movements. Subjects grasped a manipulandum using a precision grip with the tips of the thumb and index finger on either side. The grip force (normal to the contact surfaces) and the load force (tangential to the surfaces) were measured, along with the trajectory of the hand. The manipulandum was attached to two servo-controlled linear motors used to create inertial and viscous loads as well as a composite load, including inertial, viscous, and elastic components. The form of the hand trajectory was independent of load for some subjects but varied systematically across load conditions in others. Nevertheless, under all load conditions and in all subjects, grip force was modulated in parallel with, and thus anticipated, fluctuations in load force despite the marked variation in the form of the load function. This indicates that the CNS is able to predict the load force and the kinematics of hand movement on which the load depends. We suggest this prediction is based on an internal model of the motor apparatus and external load and is used to determine the grip forces required to stabilize the load.
The complex contribution of NOS interneurons in the physiology of cerebrovascular regulation

Following the discovery of the vasorelaxant properties of nitric oxide (NO) by Furchgott and Ignarro, the finding by Bredt and coll. of a constitutively expressed NO synthase in neurons (nNOS) led to the presumption that neuronal NO may control cerebrovascular functions. Consequently, numerous studies have sought to determine whether neuraly-derived NO is involved in the regulation of cerebral blood flow (CBF). Anatomically, axons, dendrites, or somata of NO neurons have been found to contact the basement membrane of blood vessels or perivascular astrocytes in all segments of the cortical microcirculation. Functionally, various experimental approaches support a role of neuronal NO in the maintenance of resting CBF as well as in the vascular response to neuronal activity. Since decades, it has been assumed that neuronal NO simply diffuses to the local blood vessels and produce vasodilation through a cGMP-PKG dependent mechanism. However, NO is not the sole mediator of vasodilation in the cerebral microcirculation and is known to interact with a myriad of signaling pathways also involved in vascular control. In addition, cerebrovascular regulation is the result of a complex orchestration between all components of the neurovascular unit (i.e., neuronal, glial, and vascular cells) also known to produce NO. In this review article, the role of NO interneuron in the regulation of cortical microcirculation will be discussed in the context of the neurovascular unit.
Genetic Interactions among the West Nile Virus Methyltransferase, the RNA-Dependent RNA Polymerase, and the 5′ Stem-Loop of Genomic RNA

ABSTRACT Flavivirus methyltransferase catalyzes both guanine N7 and ribose 2′-OH methylations of the viral RNA cap (GpppA-RNA→m7GpppAm-RNA). The methyltransferase is physically linked to an RNA-dependent RNA polymerase (RdRp) in the flaviviral NS5 protein. Here, we report genetic interactions of West Nile virus (WNV) methyltransferase with the RdRp and the 5′-terminal stem-loop of viral genomic RNA. Genome-length RNAs, containing amino acid substitutions of D146 (a residue essential for both cap methylations) in the methyltransferase, were transfected into BHK-21 cells. Among the four mutant RNAs (D146L, D146P, D146R, and D146S), only D146S RNA generated viruses in transfected cells. Sequencing of the recovered viruses revealed that, besides the D146S change in the methyltransferase, two classes of compensatory mutations had reproducibly emerged. Class 1 mutations were located in the 5′-terminal stem-loop of the genomic RNA (a G35U substitution or U38 insertion). Class 2 mutations resided in NS5 (K61Q in methyltransferase and W751R in RdRp). Mutagenesis analysis, using a genome-length RNA and a replicon of WNV, demonstrated that the D146S substitution alone was lethal for viral replication; however, the compensatory mutations rescued replication, with the highest rescuing efficiency occurring when both classes of mutations were present. Biochemical analysis showed that a low level of N7 methylation of the D146S methyltransferase is essential for the recovery of adaptive viruses. The methyltransferase K61Q mutation facilitates viral replication through improved N7 methylation activity. The RdRp W751R mutation improves viral replication through an enhanced polymerase activity. Our results have clearly established genetic interactions among flaviviral methyltransferase, RdRp, and the 5′ stem-loop of the genomic RNA.
Cry Features Reflect Pain Intensity in Term Newborns: An Alarm Threshold

The purpose of this study was to assess differences in sound spectra of crying of term newborns in relation to different pain levels. Fifty-seven consecutively born neonates were evaluated during heel-prick performed with different analgesic techniques. Crying was recorded and frequency spectrograms analyzed. A pain score on the DAN (Douleur Aiguë du Nouveau-né) scale was assigned to each baby after the sampling. Three features were considered and correlated with the corresponding DAN scores:1) whole spectral form; 2) the fundamental frequency of the first cry emitted (F0); and 3) root mean square sound pressure normalized to its maximum. After emission of the first cry, babies with DAN scores >8, but not with DAN scores ≤8 (p < 0.001), showed a pattern (“siren cry”) characterized by a sequence of almost identical cries with a period on the order of 1 s. A statistically significant correlation was found between root mean square (r2 = 89%, p < 0.01), F0 (r2 = 32%, p < 0.05), siren cry (r2 = 68.2%, p = 0.02), and DAN score. F0 did not show significant correlation with DAN score in the subset of neonates with DAN scores ≤8 (r2 = 1.4%, p = 0.94), and babies with a DAN score >8 had a significantly higher F0 than those with lower DAN scores (p = 0.016). An alarm threshold exists between high (>8) and low (≤8) DAN scores: crying has different features in these two groups. When pain exceeds a DAN score of 8, usually a first cry at a high pitch is emitted, followed by the siren cry, with a sound level maintained near its maximum.
Effects of Carbon Black and Titanium Dioxide on Ultraviolet Weathering of Wood Flour-HDPE/Lumber Composites Using Multi-phase Co-extrusion Technology

A new type of wood-plastic/lumber composite (WPLC) was fabricated with laminated veneer lumber as a core, and the traditional wood-plastic composite (WPC) as a shell layer using multi-phase co-extrusion technology. This WPLC was used to manufacture a window frame, and the effects of inorganic pigments (carbon black (CB), titanium dioxide (TiO2), and their mixtures) on the decorative effect and ultraviolet (UV) weathering performance of the shell layer of the window frame were investigated. Weathering variables included UV irradiation duration and water spraying cycles for up to 6000 h. The surface color was analyzed by spectrophotometry during weathering. In addition, a scanning electron microscopy analysis and Fourier transform infrared spectroscopy analyzed the weathering properties of the WPLC shell layer. The results showed that (1) different decorative effects (white, grey, and black color) of the window frames were achieved by incorporating CB, TiO2, and their mixture; (2) the composites incorporated with CB and/or TiO2 exhibited less discoloration and fewer surface cracks; (3) the composites with CB and TiO2 showed a better photo-stability than those with a UV stabilizer (UV326). The overall color change (△E) of the composites incorporated with UV326, TiO2, and CB was 20.0, 11.7, and 10.8, respectively, after 3000 h of weathering; and (4) a combination of CB and TiO2 showed a synergistic effect on alleviating the photo-oxidation process of the WPC shell layers, which confirmed its UV-shielding effect.
TC10 Is Regulated by Caveolin in 3T3-L1 Adipocytes

Background TC10 is a small GTPase found in lipid raft microdomains of adipocytes. The protein undergoes activation in response to insulin, and plays a key role in the regulation of glucose uptake by the hormone. Methodology/Principal Findings TC10 requires high concentrations of magnesium in order to stabilize guanine nucleotide binding. Kinetic analysis of this process revealed that magnesium acutely decreased the nucleotide release and exchange rates of TC10, suggesting that the G protein may behave as a rapidly exchanging, and therefore active protein in vivo. However, in adipocytes, the activity of TC10 is not constitutive, indicating that mechanisms must exist to maintain the G protein in a low activity state in untreated cells. Thus, we searched for proteins that might bind to and stabilize TC10 in the inactive state. We found that Caveolin interacts with TC10 only when GDP-bound and stabilizes GDP binding. Moreover, knockdown of Caveolin 1 in 3T3-L1 adipocytes increased the basal activity state of TC10. Conclusions/Significance Together these data suggest that TC10 is intrinsically active in vivo, but is maintained in the inactive state by binding to Caveolin 1 in 3T3-L1 adipocytes under basal conditions, permitting its activation by insulin.
Biochemical and Genetic Conservation of Fission Yeast Dsk1 and Human SR Protein-Specific Kinase 1

ABSTRACT Arginine/serine-rich (RS) domain-containing proteins and their phosphorylation by specific protein kinases constitute control circuits to regulate pre-mRNA splicing and coordinate splicing with transcription in mammalian cells. We present here the finding that similar SR networks exist in Schizosaccharomyces pombe. We previously showed that Dsk1 protein, originally described as a mitotic regulator, displays high activity in phosphorylating S. pombe Prp2 protein (spU2AF59), a homologue of human U2AF65. We now demonstrate that Dsk1 also phosphorylates two recently identified fission yeast proteins with RS repeats, Srp1 and Srp2, in vitro. The phosphorylated proteins bear the same phosphoepitope found in mammalian SR proteins. Consistent with its substrate specificity, Dsk1 forms kinase-competent complexes with those proteins. Furthermore,dsk1 + gene determines the phenotype ofprp2 + overexpression, providing in vivo evidence that Prp2 is a target for Dsk1. The dsk1-null mutant strain became severely sick with the additional deletion of a related kinase gene. Significantly, human SR protein-specific kinase 1 (SRPK1) complements the growth defect of the double-deletion mutant. In conjunction with the resemblance of dsk1 + andSRPK1 in sequence homology, biochemical properties, and overexpression phenotypes, the complementation result indicates that SRPK1 is a functional homologue of Dsk1. Collectively, our studies illustrate the conserved SR networks in S. pombe consisting of RS domain-containing proteins and SR protein-specific kinases and thus establish the importance of the networks in eucaryotic organisms.
Introduction of Inactivated Poliovirus Vaccine and Impact on Vaccine-Associated Paralytic Poliomyelitis — Beijing, China, 2014–2016

When included in a sequential polio vaccination schedule, inactivated polio vaccine (IPV) reduces the risk for vaccine-associated paralytic poliomyelitis (VAPP), a rare adverse event associated with receipt of oral poliovirus vaccine (OPV). During January 2014, the World Health Organization (WHO) recommended introduction of at least 1 IPV dose into routine immunization schedules in OPV-using countries (1). The Polio Eradication and Endgame Strategic Plan 2013-2018 recommended completion of IPV introduction in 2015 and globally synchronized withdrawal of OPV type 2 in 2016 (2). Introduction of 1 dose of IPV into Beijing's Expanded Program on Immunization (EPI) on December 5, 2014 represented China's first province-wide IPV introduction. Coverage with the first dose of polio vaccine was maintained from 96.2% to 96.9%, similar to coverage with the first dose of diphtheria and tetanus toxoids and pertussis vaccine (DTP) (96.5%-97.2%); the polio vaccine dropout rate (the percentage of children who received the first dose of polio vaccine but failed to complete the series) was 1.0% in 2015 and 0.4% in 2016. The use of 3 doses of private-sector IPV per child decreased from 18.1% in 2014, to 17.4% in 2015, and to 14.8% in 2016. No cases of VAPP were identified during 2014-2016. Successful introduction of IPV into the public sector EPI program was attributed to comprehensive planning, preparation, implementation, robust surveillance for adverse events after immunization (AEFI), and monitoring of vaccination coverage. This evaluation provided information that helped contribute to the expansion of IPV use in China and in other OPV-using countries.
A New Sparse Representation of Seismic Data Using Adaptive Easy-Path Wavelet Transform

Sparse representation of seismic data is a crucial step for seismic forward modeling and seismic processing such as coherent noise separation, imaging, and sparsity-promoting data recovery. In this letter, a new locally adaptive wavelet transform, called easy-path wavelet transform (EPWT), is applied for the sparse representation of seismic data. The EPWT is an adaptive geometric wavelet transform that works along a series of special pathways through the input data and exploits the local correlations of the data. The transform consists of two steps: reorganizing the data following the pathways according to the data values and then applying a 1-D wavelet transform along the pathways. This leads to a very sparse wavelet representation. In comparison to conventional wavelets, the EPWT concentrates most of the energy of signals at smooth scales and needs less significant wavelet coefficients to represent signals. Numerical experiments show that the new method is really superior over the conventional wavelets and curvelets in terms of sparse representation and compression of seismic data.
Accelerated Progression From Mild Cognitive Impairment to Dementia in People With Diabetes

OBJECTIVE The effect of diabetes on mild cognitive impairment (MCI) and its conversion to dementia remains controversial. We sought to examine whether diabetes and pre-diabetes are associated with MCI and accelerate the progression from MCI to dementia. RESEARCH DESIGN AND METHODS In the Kungsholmen Project, 963 cognitively intact participants and 302 subjects with MCI (120 with amnestic MCI [aMCI ] and 182 with other cognitive impairment no dementia [oCIND]) age ≥75 years were identified at baseline. The two cohorts were followed for 9 years to detect the incident MCI and dementia following international criteria. Diabetes was ascertained based on a medical examination, hypoglycemic medication use, and random blood glucose level ≥11.0 mmol/l. Pre-diabetes was defined as random blood glucose level of 7.8–11.0 mmol/l in diabetes-free participants. Data were analyzed using standard and time-dependent Cox proportional-hazards models. RESULTS During the follow-up period, in the cognitively intact cohort, 182 people developed MCI (42 aMCI and 140 oCIND), and 212 developed dementia. In the MCI cohort, 155 subjects progressed to dementia, the multi-adjusted hazard ratio (95% CI) of dementia was 2.87 (1.30–6.34) for diabetes, and 4.96 (2.27–10.84) for pre-diabetes. In a Kaplan-Meier survival analysis, diabetes and pre-diabetes accelerated the progression from MCI to dementia by 3.18 years. Diabetes and pre-diabetes were neither cross-sectionally nor longitudinally associated with MCI. CONCLUSIONS Diabetes and pre-diabetes substantially accelerate the progression from MCI to dementia, and anticipate dementia occurrence by more than 3 years in people with MCI. The association of diabetes with the development of MCI is less evident in old people.
Mean shift based clustering in high dimensions: a texture classification example

Feature space analysis is the main module in many computer vision tasks. The most popular technique, k-means clustering, however, has two inherent limitations: the clusters are constrained to be spherically symmetric and their number has to be known a priori. In nonparametric clustering methods, like the one based on mean shift, these limitations are eliminated but the amount of computation becomes prohibitively large as the dimension of the space increases. We exploit a recently proposed approximation technique, locality-sensitive hashing (LSH), to reduce the computational complexity of adaptive mean shift. In our implementation of LSH the optimal parameters of the data structure are determined by a pilot learning procedure, and the partitions are data driven. As an application, the performance of mode and k-means based textons are compared in a texture classification study.
Characterization of Pseudomonas aeruginosa Exoenzyme S as a Bifunctional Enzyme in J774A.1 Macrophages

ABSTRACT Pseudomonas aeruginosa exoenzyme S (ExoS) is a type III secretion (TTS) effector, which includes both a GTPase-activating protein (GAP) activity toward the Rho family of low-molecular-weight G (LMWG) proteins and an ADP-ribosyltransferase (ADPRT) activity that targets LMWG proteins in the Ras, Rab, and Rho families. The coordinate function of both activities of ExoS in J774A.1 macrophages was assessed by using P. aeruginosa strains expressing and translocating wild-type ExoS or ExoS defective in GAP and/or ADPRT activity. Distinct and coordinated functions were identified for both domains. The GAP activity was required for the antiphagocytic effect of ExoS and was linked to interference of lamellopodium and membrane ruffle formation. Alternatively, the ADPRT activity of ExoS altered cellular adherence and morphology and was linked to effects on filopodium formation. The cellular mechanism of ExoS GAP activity included an inactivation of Rac1 function, as determined in p21-activated kinase 1-glutathione S-transferase (GST) pull-down assays. The ADPRT activity of ExoS targeted Ras and RalA but not Rab or Rho proteins, and Ral binding protein 1-GST pull-down assays identified an effect of ExoS ADPRT activity on RalA activation. The results from these studies confirm the bifunctional nature of ExoS activity within macrophages when translocated by TTS.
Longterm outcomes in patients with giant aneurysms secondary to Kawasaki disease.

OBJECTIVE Kawasaki disease (KD) has potentially serious cardiac complications including coronary artery aneurysms. Children who develop giant aneurysms (GA) are at increased risk of thrombosis and ischemia, and although longterm oral anticoagulation with warfarin is recommended, its efficacy has not been studied. We examined the longterm outcome of patients with GA secondary to KD, to determine if anticoagulation with warfarin aids in the prevention of myocardial ischemia. METHODS We studied patients with KD followed between May 1990 and April 2000. RESULTS Thirty-nine GA occurred in 2.2% of patients with KD (22/997 patients), and 33 non-GA were also identified in these patients. Patients were divided into 2 groups, those taking warfarin and no warfarin. Most patients in both groups were also taking antiplatelet agents. The demographics of the 2 groups were statistically similar, except the median duration of followup was significantly longer for patients in the no-warfarin group (6.9 vs 13.3 yrs; p = 0.008). Four early ischemic events (< 1 year after KD diagnosis) occurred (3 myocardial infarctions and one stroke). Screening for late ischemic events by stress nuclear medicine myocardial perfusion imaging revealed only one patient, in the no-warfarin group, with reversible perfusion defects. No patient had clinical signs or symptoms of late myocardial ischemia. Echocardiographic regression of aneurysms was observed in both groups. In the warfarin vs no-warfarin group, the diameters of the GA regressed a median 22% vs 32% (p = 0.27), and non-GA regressed a median of 30% vs 25% (p = 0.61). Compliance with anticoagulation was good, and no major bleeding complication of anticoagulation occurred. CONCLUSION Regression of GA occurred in most of our patients, and minimal late ischemia was observed. Further studies are required to evaluate the use of oral anticoagulation in patients with GA secondary to KD.