Miracle-dz/UniFAR-FTUs huggingface dataset:
The activity of monkey thalamic and motor cortical neurones in a skilled, ballistic movement.

1. Three monkeys were trained to perform a reaction‐time task of the wrist and single‐cell recordings were made from the motor cortex (eighty‐four cells), ventro‐posterior lateralis par caudalis (VPLc) (forty‐two cells) and cerebellar thalamus (seventy‐seven cells). 2. The majority (43/77, 56%) of cerebellar thalamic neurones fired phasically during movement, whereas in the motor cortex most neurones (53/84, 64%) had a phasic‐tonic discharge pattern. Most neurones in both locations discharged in relation to the direction of movement (reciprocal pattern). 3. The cerebellar thalamus is unlike the motor cortex in that it does not usually encode a signal for force or joint position in its discharge. 4. Twenty‐two per cent (17/77) of cerebellar thalamic neurones had a period of reduced discharge rate before the phasic burst of activity, and represent a pattern of discharge not seen in motor cortex or VPLc neurones. 5. The onset of phasic activity in the cerebellar thalamus was significantly later (average 94 ms) than in the motor cortex but occurred just before electromyogram (EMG) activity. The phasic activity in the cerebellar thalamus usually ended before the phasic component of motor cortex discharge was completed. 6. Phasic activity in VPLc neurones commenced after the onset of EMG discharge and on average 26 ms after the commencement of movement. Most neurones with deep sensory receptive fields fired with a reciprocal pattern, while neurones with cutaneous fields usually fixed bidirectionally in relation to the task. Almost one‐third of neurones signalled force and a similar number had discharge levels that encoded characteristics of the joint position. 7. The duration of discharge of VPLc neurones during the voluntary movement was marginally less than the duration of the movement velocity peak and the VPLc may therefore be signalling the duration of the velocity. Phasic activity in cerebellar thalamic neurones fired for a duration similar to the VPLc neurones, but commenced before the movement. Therefore, if the cerebellar thalamus is carrying information about the duration of the velocity, it does so before the movement starts. 8. The phasic burst of activity in cells of the cerebellar thalamus is timed so that it can contribute to the later component of the phasic burst of motor cortical discharge. Thus we speculate that in skilled, ballistic movements, the cerebellum may provide a response which travels via the cerebellar thalamus and helps to determine the magnitude and duration of the phasic part of cortical discharge. (ABSTRACT TRUNCATED AT 400 WORDS)
Membrane traffic in myelinating oligodendrocytes

In the central nervous system (CNS), the myelin sheath is synthesised by oligodendrocytes as a specialised subdomain of an extended plasma membrane, reminiscent of the segregated membrane domains of polarised cells. Myelination takes place within a relatively short period of time and oligodendrocytes must have adapted membrane sorting and transport mechanisms to achieve such a high rate of myelin synthesis and to maintain the unique organisation of the myelin membrane. In adult life, maintenance of the functional myelin sheath requires a carefully orchestrated balance of myelin synthesis and turnover. Imbalance in these processes may cause dys‐ or demyelination and disease. This review summarises what is currently known about myelin protein trafficking and mistrafficking in oligodendrocytes. We also present data demonstrating distinct transport pathways for myelin structural proteins and the expression of SNARE proteins in differentiating oligodendrocytes. Myelinating glial cells may well serve as a model system for studying general aspects of membrane trafficking and organisation of membrane domains. Microsc. Res. Tech. 52:656–671, 2001. © 2001 Wiley‐Liss, Inc.
Rational use of antiretroviral therapy in low-income and middle-income countries: optimizing regimen sequencing and switching

This editorial reviews objective is to support the development of strategies to maximize the effectiveness of first-line and second-line antiretroviral therapy (ART) regimens and optimize the training of regimen switching in lower-income and middle-income countries (LMICs). The support is required to fully utilize the survival benefit of available treatment options maintain program cost-effectiveness and enable achievement of universal access to HIV treatment and states that the comprehensive strategy must be evidence based and focused on the rational long-term use of ART at a population level.
Multi-objective optimization of energy generation and noise propagation: A hybrid approach

Various methodologies have been proposed to optimally place wind turbines inside a wind farm to extract maximum energy. However it is highly likely, that these layouts come in the proximity of human habitation leading to a negative impact on their health by creating noise, visual impact, electromagnetic interference etc. Compared to others, noise has become an important point of concern for wind farm owners, which limits the number of turbines to be erected in a wind farm satisfying its mandatory noise limits. In this study, wind farm layout optimization (WFLO) is performed by considering a trade-off between energy and noise generated in a wind farm. A novel hybrid methodology is proposed to carry out a multi-objective optimization between maximized energy and minimized noise level value. Proposed hybrid methodology is a combination of multi-objective evolutionary algorithm (NSGA-II) followed by a single objective gradient approach to solve a series of integer and continuous problem formulations. Results of a generated Pareto Optimal (PO) front provide an alternative solution of Energy - Noise trade-off along with an additional information on corresponding optimum number of turbines and their optimal location coordinates, which leaves a designer with ample of choices to make in between optimal turbine number as well as two objectives.
Association between ambient air pollution and health-related quality of life in Japan: Ecological study

Abstract To assess the association between air pollution and health-related quality of life (HRQOL), we performed an ecological study by a two-stage stratified random sampling of the Japanese general population. A total of 3395 subjects, aged 16 and older, filled out questionnaires, including the Medical Outcomes Study Short Form-36 Health Survey (SF-36). Air pollutants examined in this study were nitrogen oxides (NOx) and suspended particulate matter (SPM). We used analysis of covariance to estimate the mean differences for each SF-36 domain among four groups categorized according to concentrations of air pollutants to which they were exposed. We observed a significant linear trend of a lower ‘vitality’ domain score in the SF-36 in groups exposed to higher concentrations of NOx (p = 0.013). The results of the present study are important for, and needed by, public health policy makers, because assessing the health effects of air pollution by measuring the HRQOL would provide a new method for formulating air pollution policies.
Predicting the birth characteristics of normal fetuses 14 weeks before delivery

This investigation has evaluated the ability of Rossavik growth models (derived from data obtained before 26 weeks) to predict birth characteristics in normal fetuses (assuming no growth after 38 weeks). Both weight and head circumference were predicted without systematic errors and the ranges of the random errors were approximately ±10% and ±5%, respectively. A range of approximately ±10% for the random error was also found for the abdominal and thigh circumferences, but both parameters were systematically overestimated (17.3% and 6.4%, respectively). No evidence of a relationship between the percent deviation and age at delivery (up to 41 weeks) was found for any of the parameters studied.
Prognostic significance of serum albumin level changes in acute ischemic stroke: the role of biological and analytical variation

Abstract Background: Animal studies have shown a neuroprotective effect of human serum albumin (sAlb) in ischemic stroke (IS). Previous studies have shown an association of high sAlb with better outcome. Our aim is to investigate the kinetics of sAlb in acute IS and its possible correlation with outcome taking into account the analytical and biological variation of sAlb measurement. Methods: In a prospective observational study, we enrolled 105 patients with acute IS. sAlb was measured upon admission, at 24 h, 48 h, 72 h and Day 7 thereafter. Stroke severity was assessed upon admission and at 72 h, and functional outcome on Day 7. Patients were divided into two groups according to functional outcome on discharge. Calculation of reference change value was used to assess the clinical significance of sAlb changes and multiple logistic regression to assess the independent association between variables and outcome. Results: Fifty-one patients (48.6%) had poor outcome. Their sAlb levels exhibit a significant daily decrease until 72 h (35.9 g/L) compared to baseline (41.1 g/L) and remained low until Day 7 (36.0 g/L). These changes were clinically significant only from 72 h on. Among non-poor outcome patients a significant daily decrease until 72 h (40.9 g/L) was followed by recovery on Day 7 (41.2 g/L), but these changes were not clinically significant. sAlb was not independently associated with the functional outcome at any time-point. Conclusions: This study shows that sAlb levels might change during the first days after an acute IS, but these changes although statistically significant are not clinically significant if we take into account the analytical and biological variation of sAlb.
Mutations in Nu1, the gene encoding the small subunit of bacteriophage lambda terminase, suppress the postcleavage DNA packaging defect of cosB mutations

The linear double-stranded DNA molecules in lambda virions are generated by nicking of concatemeric intracellular DNA by terminase, the lambda DNA packaging enzyme. Staggered nicks are introduced at cosN to generate the cohesive ends of virion DNA. After nicking, the cohesive ends are separated by terminase; terminase bound to the left end of the DNA to be packaged then binds the empty protein shell, i.e., the prohead, and translocation of DNA into the prohead occurs. cosB, a site adjacent to cosN, is a terminase binding site. cosB facilitates the rate and fidelity of the cosN cleavage reaction by serving as an anchoring point for gpNu1, the small subunit of terminase. cosB is also crucial for the formation of a stable terminase-DNA complex, called complex I, formed after cosN cleavage. The role of complex I is to bind the prohead. Mutations in cosB affect both cosB functions, causing mild defects in cosN cleavage and severe packaging defects. The lethal cosB R3- R2- R1- mutation contains a transition mutation in each of the three gpNu1 binding sites of cosB. Pseudorevertants of lambda cosB R3- R2- R1- DNA contain suppressor mutations affecting gpNu1. Results of experiments that show that two such suppressors, Nu1ms1 and Nu1ms3, do not suppress the mild cosN cleavage defect caused by the cosB R3- R2- R1- mutation but strongly suppress the DNA packaging defect are presented. It is proposed that the suppressing terminases, unlike the wild-type enzyme, are able to assemble a stable complex I with cosB R3- R2- R1- DNA. Observations on the adenosine triphosphatase activities and protease susceptibilities of gpNu1 of the Nu1ms1 and Nu1ms3 terminases indicate that the conformation of gpNu1 is altered in the suppressing terminases.
Consensus rank orderings of molecular fingerprints illustrate the ‘most genuine’ similarities between marketed drugs and small endogenous human metabolites, but highlight exogenous natural products as the most important ‘natural’ drug transporter substrates

We compare several molecular fingerprint encodings for marketed, small molecule drugs, and assess how their rank order varies with the fingerprint in terms of the Tanimoto similarity to the most similar endogenous human metabolite as taken from Recon2. For the great majority of drugs, the rank order varies very greatly depending on the encoding used, and also somewhat when the Tanimoto similarity (TS) is replaced by the Tversky similarity. However, for a subset of such drugs, amounting to some 10% of the set and a Tanimoto similarity of ~0.8 or greater, the similarity coefficient is relatively robust to the encoding used. This leads to a metric that, while arbitrary, suggests that a Tanimoto similarity of 0.75-0.8 or greater genuinely does imply a considerable structural similarity of two molecules in the drug-endogenite space. Although comparatively few (<10% of) marketed drugs are, in this sense, robustly similar to an endogenite, there is often at least one encoding with which they are genuinely similar (e.g. TS > 0.75). This is referred to as the Take Your Pick Improved Cheminformatic Analytical Likeness or TYPICAL encoding, and on this basis some 66% of drugs are within a TS of 0.75 to an endogenite. We next explicitly recognise that natural evolution will have selected for the ability to transport dietary substances, including plant, animal and microbial ‘secondary’ metabolites, that are of benefit to the host. These should also be explored in terms of their closeness to marketed drugs. We thus compared the TS of marketed drugs with the contents of various databases of natural products. When this is done, we find that some 80% of marketed drugs are within a TS of 0.7 to a natural product, even using just the MACCS encoding. For patterned and TYPICAL encodings, 80% and 98% of drugs are within a TS of 0.8 to (an endogenite or) an exogenous natural product. This implies strongly that it is these exogeneous (dietary and medicinal) natural products that are more to be seen as the ‘natural’ substrates of drug transporters (as is recognised, for instance, for the solute carrier SLC22A4 and ergothioneine). This novel analysis casts an entirely different light on the kinds of natural molecules that are to be seen as most like marketed drugs, and hence potential transporter substrates, and further suggests that a renewed exploitation of natural products as drug scaffolds would be amply rewarded.
A randomized, double-blind, placebo-controlled 26-week trial of aripiprazole in recently manic patients with bipolar I disorder.

OBJECTIVE To investigate the safety and efficacy of aripiprazole in preventing relapse of a mood episode in recently manic- or mixed-episode patients with bipolar I disorder stabilized on aripiprazole. METHOD This randomized, double-blind, parallel-group, placebo-controlled, multicenter study enrolled patients from 76 centers in 3 countries (Argentina, Mexico, United States) from March 2000 to June 2003. Bipolar I disorder (DSM-IV) patients who had recently been hospitalized and treated for a manic or mixed episode entered an open-label stabilization phase (aripiprazole monotherapy: 15 or 30 mg/day, 6-18 weeks). After meeting stabilization criteria (Young Mania Rating Scale score of < or = 10 and Montgomery-Asberg Depression Rating Scale score of < or = 13 for 6 consecutive weeks), 161 patients were randomly assigned to aripiprazole or placebo for the 26-week, double-blind phase. The primary endpoint was time to relapse for a manic, mixed, or depressive episode (defined by discontinuation caused by lack of efficacy). RESULTS Aripiprazole was superior to placebo in delaying the time to relapse (p = .020). Aripiprazole-treated patients had significantly fewer relapses (25%) than placebo patients (43%; p = .013). Aripiprazole was superior to placebo in delaying the time to manic relapse (p = .01); however, no significant differences were observed in time to depressive relapse (p = .68). Weight gain (> or = 7% increase) occurred in 7 (13%) aripiprazole-treated and 0 placebo-treated patients. Adverse events (> or = 5% incidence and twice that of placebo) reported by aripiprazole-treated patients were akathisia, pain in the extremities, tremor, and vaginitis. CONCLUSIONS Aripiprazole, 15 or 30 mg/day, was superior to placebo in maintaining efficacy in patients with bipolar I disorder with a recent manic or mixed episode who were stabilized and maintained on aripiprazole treatment for 6 weeks, as shown by a longer time to relapse.
Evaluation of carotenoids and reactive oxygen species in human skin after UV irradiation: a critical comparison between in vivo and ex vivo investigations

UV irradiation is one of the most harmful exogenous factors for the human skin. In addition to the development of erythema, free radicals, that is reactive oxygen species (ROS), are induced under its influence and promote the development of oxidative stress in the skin. Several techniques are available for determining the effect of UV irradiation. Resonance Raman spectroscopy (RRS) measures the reduction of the carotenoid concentration, while electron paramagnetic resonance (EPR) spectroscopy enables the analysis of the production of free radicals. Depending on the method, the skin parameters are analysed in vivo or ex vivo. This study provides a critical comparison between in vivo and ex vivo investigations on the ROS formation and carotenoid depletion caused by UV irradiation in human skin. The oxygen content of tissue was also determined. It was shown that the antioxidant status measured in the skin samples in vivo and ex vivo was different. The depletion in the carotenoid concentration in vivo exceeded the value determined ex vivo by a factor of about 1.5, and the radical formation after UV irradiation was significantly greater in vivo by a factor of 3.5 than that measured in excised human skin, which can be explained by the lack of oxygen ex vivo.
The Cardio‐Protective Properties of Ncx‐6550, a Nitric Oxide Donating Pravastatin, in the Mouse

Please cite this paper as: Di Filippo, Monopoli, Ongini, Perretti and D’Amico (2010). The Cardio‐Protective Properties of Ncx‐6550, a Nitric Oxide Donating Pravastatin, in the Mouse. Microcirculation17(6), 417–426.
glomerular disease Loss of endogenous thymosin b 4 accelerates

Elisavet Vasilopoulou, Maria Kolatsi-Joannou, Maja T. Lindenmeyer, Kathryn E. White, Michael G. Robson, Clemens D. Cohen, Neil J. Sebire, Paul R. Riley, Paul J. Winyard and David A. Long Developmental Biology and Cancer Programme, UCL Institute of Child Health, London, United Kingdom; Nephrological Center, Medical Clinic and Policlinic IV, University of Munich, Munich, Germany; EM Research Services, University of Newcastle, Newcastle upon Tyne, United Kingdom; MRC Centre for Transplantation, King’s College London, London, United Kingdom; and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
Thymidylate synthase gene variants as predictors of clinical response and toxicity to fluoropyrimidine-based chemotherapy for colorectal cancer

Abstract Background: Fluoropyrimidines form the chemotherapy backbone of advanced and metastatic colorectal cancer (CRC). These drugs are frequently associated with toxicity events that result in dose adjustments and even suspension of the treatment. The thymidylate synthase (TYMS) gene is a potential marker of response and toxicity to fluoropyirimidines as this enzyme is the molecular target of these drugs. Our aim was to assess the association between variants of TYMS with response and toxicity to fluoropyrimidines in patients with CRC in independent retrospective and prospective studies. Methods: Variants namely rs45445694, rs183205964, rs2853542 and rs151264360 of TYMS were genotyped in 105 CRC patients and were evaluated to define their association with clinical response and toxicity to fluoropyrimidines. Additionally, the relationship between genotypes and tumor gene expression was analyzed by quantitative polymerase chain reaction. Results: The 2R/2R (rs45445694) was associated with clinical response (p=0.05, odds ratio (OR)=3.45) and severe toxicity (p=0.0014, OR=5.21, from pooled data). Expression analysis in tumor tissues suggested a correlation between the 2R/2R genotype and low TYMS expression. Conclusions: The allele 2R (rs45445694) predicts severe toxicity and objective response in advanced CRC patients. In addition, the alleles G(rs2853542) and 6bp-(rs151264360) are independent predictors of response failure to chemotherapy. This is the first study made on a Latin American population that points out TYMS gene variants have predictive values for response and toxicity in patients with CRC treated with fluoropyrimidine-based chemotherapy.
Bordetella Type III Secretion and Adenylate Cyclase Toxin Synergize to Drive Dendritic Cells into a Semimature State1

Bordetella bronchiseptica establishes persistent infection of the murine respiratory tract. We hypothesize that long-term colonization is mediated in part by bacteria-driven modulation of dendritic cells (DCs) leading to altered adaptive immune responses. Bone marrow-derived DCs (BMDCs) from C57BL/6 mice infected with live B. bronchiseptica exhibited high surface expression of MHCII, CD86, and CD80. However, B. bronchiseptica-infected BMDCs did not exhibit significant increases in CD40 surface expression and IL-12 secretion compared with BMDCs treated with heat-killed B. bronchiseptica. The B. bronchiseptica type III secretion system (TTSS) mediated the increase in MHCII, CD86, and CD80 surface expression, while the inhibition of CD40 and IL-12 expression was mediated by adenylate cyclase toxin (ACT). IL-6 secretion was independent of the TTSS and ACT. These phenotypic changes may result from differential regulation of MAPK signaling in DCs. Wild-type B. bronchiseptica activated the ERK 1/2 signaling pathway in a TTSS-dependent manner. Additionally, ACT was found to inhibit p38 signaling. These data suggest that B. bronchiseptica drive DC into a semimature phenotype by altering MAPK signaling. These semimature DCs may induce tolerogenic immune responses that allow the persistent colonization of B. bronchiseptica in the host respiratory tract.
Endovascular treatment for chronic pulmonary hypertension: a focus on angioplasty for chronic thromboembolic pulmonary hypertension

ABSTRACT Introduction: Percutaneous transluminal pulmonary angioplasty (PTPA) was introduced for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) in the late 20th century, and first attempts in collective patients were made in 2001 with beneficial effects but a moderate amount of complications. It was refined around 2010, and has been recently established as an effective and safe treatment. Areas covered: The indication was originally inoperable CTEPH with peripheral lesions, but has now widened to symptomatic or hypoxic patients. The lesion is typically a meshwork-like structure of organized thrombi and is sometimes not seen as a stenosis angiographically, necessitating other means of investigation such as measurement of distal pressure. The technique to treat lesions is the same as for coronary angioplasty except in several ways. Expert commentary: The effects of PTPA are comparable to those of surgical endarterectomy, and the complications of reperfusion pulmonary edema and vascular injury are now controlled by several strategies and based on experience.