Miracle-dz/UniFAR-FTUs huggingface dataset:
The A 3243 G tRNALeu ( UUR ) MELAS mutation causes amino acid misincorporation and a combined respiratory chain assembly defect partially suppressed by overexpression of EFTu and EFG 2

The majority of patients with MELAS (mitochondrial encephalomyophathy, lactic acidosis, stroke-like episodes) carry a heteroplasmic A3243G mutation in the mitochondrial tRNA. The mutation prevents modification of the wobble U base, impairing translation at UUA and UUG codons; however, whether this results in amino acid misincorporation in the mitochondrial translation products remains controversial. We tested this hypothesis in homoplasmic mutant myoblasts isolated from a MELAS patient and investigated whether overexpression of the mitochondrial translation elongation factors could suppress the translation defect. Blue-Native gel electrophoretic analysis demonstrated an almost complete lack of assembly of respiratory chain complexes I, IV and V in MELAS myoblasts. This phenotype could be partially suppressed by overexpression of EFTu or EFG2 but not EFTs or EFG1. Despite the severity of the assembly defect, overall mitochondrial protein synthesis was only moderately affected, but some anomalously migrating translation products were present. Pulse-chase labeling showed reduced stability of all mitochondrial translation products consistent with the assembly defect. Labeling patterns of the translation products were similar with [H]-leucine or [H]-phenylalanine, showing that loss of the wobble U modification did not permit decoding of UUY codons; however, endoproteinase fingerprint analysis showed clear evidence of amino acid misincorporation in three polypeptides: CO III, CO II and ATP6. Taken together, these data demonstrate that the A3243G mutation produces both lossand gain-of-function phenotypes, explaining the apparent discrepancy between the severity of the translation and respiratory chain assembly defects, and suggest a function for EFG2 in quality control of translation elongation.
Variation among species in proteomic sulphur content is related to environmental conditions

The elemental composition of proteins influences the quantities of different elements required by organisms. Here, we considered variation in the sulphur content of whole proteomes among 19 Archaea, 122 Eubacteria and 10 eukaryotes whose genomes have been fully sequenced. We found that different species vary greatly in the sulphur content of their proteins, and that average sulphur content of proteomes and genome base composition are related. Forces contributing to variation in proteomic sulphur content appear to operate quite uniformly across the proteins of different species. In particular, the sulphur content of orthologous proteins was frequently correlated with mean proteomic sulphur contents. Among prokaryotes, proteomic sulphur content tended to be greater in anaerobes, relative to non-anaerobes. Thermophiles tended to have lower proteomic sulphur content than non-thermophiles, consistent with the thermolability of cysteine and methionine residues. This work suggests that persistent environmental growth conditions can influence the evolution of elemental composition of whole proteomes in a manner that may have important implications for the amount of sulphur used by living organisms to build proteins. It extends previous studies that demonstrated links between transient changes in environmental conditions and the elemental composition of subsets of proteins expressed under these conditions.
PspA Protects Streptococcus pneumoniae from Killing by Apolactoferrin, and Antibody to PspA Enhances Killing of Pneumococci by Apolactoferrin

ABSTRACT Lactoferrin is an important component of innate immunity through its sequestration of iron, bactericidal activity, and immune modulatory activity. Apolactoferrin (ALF) is the iron-depleted form of lactoferrin and is bactericidal against pneumococci and several other species of bacteria. We observed that lactoferricin (LFN), an 11-amino-acid peptide from the N terminus of lactoferrin, is bactericidal for Streptococcus pneumoniae. Strains of S. pneumoniae varied in their susceptibility to ALF. Lactoferrin is bound to the pneumococcal surface by pneumococcal surface protein A (PspA). Using mutant PspA− pneumococci of four different strains, we observed that PspA offers significant protection against killing by ALF. Knockout mutations in genes for two other choline-binding proteins (PspC and PcpA) did not affect killing by ALF. PspA did not have to be attached to the bacterial surface to inhibit killing, because the soluble recombinant N-terminal half of PspA could prevent killing by both ALF and LFN. An 11-amino-acid fragment of PspA was also able to reduce the killing by LFN. Antibody to PspA enhanced killing by lactoferrin. These findings suggested that the binding of ALF to PspA probably blocks the active site(s) of ALF that is responsible for killing.
Style Imitation and Chord Invention in Polyphonic Music with Exponential Families

Modeling polyphonic music is a particularly challenging task because of the intricate interplay between melody and harmony. A good model should satisfy three requirements: statistical accuracy (capturing faithfully the statistics of correlations at various ranges, horizontally and vertically), flexibility (coping with arbitrary user constraints), and generalization capacity (inventing new material, while staying in the style of the training corpus). Models proposed so far fail on at least one of these requirements. We propose a statistical model of polyphonic music, based on the maximum entropy principle. This model is able to learn and reproduce pairwise statistics between neighboring note events in a given corpus. The model is also able to invent new chords and to harmonize unknown melodies. We evaluate the invention capacity of the model by assessing the amount of cited, re-discovered, and invented chords on a corpus of Bach chorales. We discuss how the model enables the user to specify and enforce user-defined constraints, which makes it useful for style-based, interactive music generation.
Draft Genome Sequence of the Sexually Transmitted Pathogen Trichomonas vaginalis

We describe the genome sequence of the protist Trichomonas vaginalis, a sexually transmitted human pathogen. Repeats and transposable elements comprise about two-thirds of the ∼160-megabase genome, reflecting a recent massive expansion of genetic material. This expansion, in conjunction with the shaping of metabolic pathways that likely transpired through lateral gene transfer from bacteria, and amplification of specific gene families implicated in pathogenesis and phagocytosis of host proteins may exemplify adaptations of the parasite during its transition to a urogenital environment. The genome sequence predicts previously unknown functions for the hydrogenosome, which support a common evolutionary origin of this unusual organelle with mitochondria.
Cryogenic Treatment of Tool Materials: A Review

Cryogenic treatment (CT) of materials has shown significant improvement in their properties. Various advantages like increase in wear resistance, reduced residual stresses, increase in hardness, fatigue resistance, toughness imparted by transformation of retained austenite to martensite, precipitation of carbides, eta-carbide formation, perfect distributed/homogenous crystal structure, better thermal conductivity, and reduced chemical degradation. Moreover, this technology is an eco-friendly, nontoxic, and nonexplosive. Different approaches have been applied for CT to study the effect on different types of steel and other materials. In recent years, researchers have tried to evaluate the process to optimize the parameters. This paper brings out the comprehensive analysis of the strategies followed in CTs and their significant effects on properties of materials by differentiating CT from cryogenic conditioning of the process. The final part of the paper discusses the developments and outlines the trends for further research in this field.
Immune Response to Recombinant Adenovirus in Humans: Capsid Components from Viral Input Are Targets for Vector-Specific Cytotoxic T Lymphocytes

ABSTRACT We previously demonstrated that a single injection of 109 PFU of recombinant adenovirus into patients induces strong vector-specific immune responses (H. Gahéry-Ségard, V. Molinier-Frenkel, C. Le Boulaire, P. Saulnier, P. Opolon, R. Lengagne, E. Gautier, A. Le Cesne, L. Zitvogel, A. Venet, C. Schatz, M. Courtney, T. Le Chevalier, T. Tursz, J.-G. Guillet, and F. Farace, J. Clin. Investig. 100:2218–2226, 1997). In the present study we analyzed the mechanism of vector recognition by cytotoxic T lymphocytes (CTL). CD8+ CTL lines were derived from two patients and maintained in long-term cultures. Target cell infections with E1-deleted and E1-plus E2-deleted adenoviruses, as well as transcription-blocking experiments with actinomycin D, revealed that host T-cell recognition did not require viral gene transcription. Target cells treated with brefeldin A were not lysed, indicating that viral input protein-derived peptides are associated with HLA class I molecules. Using recombinant capsid component-loaded targets, we observed that the three major proteins could be recognized. These results raise the question of the use of multideleted adenoviruses for gene therapy in the quest to diminish antivector CTL responses.
Interaction of Stoned and Synaptotagmin in Synaptic Vesicle Endocytosis

The Drosophila dicistronic stonedlocus encodes two distinctive presynaptic proteins, Stoned A (STNA) and Stoned B (STNB); STNA is a novel protein without homology to known synaptic proteins, and STNB contains a domain with homology to the endocytotic protein AP50. Both Stoned proteins colocalize precisely with endocytotic proteins including the AP2 complex and Dynamin in the “lattice network” characteristic of endocytotic domains in Drosophila presynaptic terminals. FM1–43 dye uptake studies in stoned mutants demonstrate a striking decrease in the size of the endo–exo-cycling synaptic vesicle pool and loss of spatial regulation of the vesicular recycling intermediates. Mutant synapses display a significant delay in vesicular membrane retrieval after depolarization and neurotransmitter release. These studies suggest that the Stoned proteins play a role in mediating synaptic vesicle endocytosis. We have documented previously a highly specific synaptic mislocalization and degradation of Synaptotagmin I instoned mutants. Here we show that transgenic overexpression of Synaptotagmin I rescues stonedembryonic lethality and restores endocytotic recycling to normal levels. Furthermore, overexpression of Synaptotagmin I in otherwise wild-type animals results in increased synaptic dye uptake, indicating that Synaptotagmin I directly regulates the endo–exo-cycling synaptic vesicle pool size. In parallel with recent biochemical studies, this genetic analysis strongly suggests that Stoned proteins regulate the AP2–Synaptotagmin I interaction during synaptic vesicle endocytosis. We conclude that Stoned proteins control synaptic transmission strength by mediating the retrieval of Synaptotagmin I from the plasma membrane.
Amiodarone and the thyroid: a practical guide to the management of thyroid dysfunction induced by amiodarone therapy

Amiodarone induces predictable changes in thyroid function tests that are largely explicable in terms of the physiological effects of iodide excess and inhibition of deiodinase activity. Clinically relevant thyroid dysfunction is not uncommon during amiodarone therapy, and requires careful diagnosis and treatment. The diagnosis and management of thyrotoxicosis is probably best supervised by a specialist endocrinologist. Control of hypothyroidism can generally be achieved simply by the addition of T4 to the therapeutic regimen, ideally after an initial assessment by an endocrinologist. The frequency with which amiodarone causes thyroid and other complications serves to emphasize the need for rational prescribing and long-term cardiological follow up.
Canadian Experiment for Soil Moisture in 2010 (CanEx-SM10): Overview and Preliminary Results

The Canadian Experiment for Soil Moisture in 2010 (CanEx-SM10) was carried out in Saskatchewan, Canada, from 31 May to 16 June, 2010. Its main objective was to contribute to Soil Moisture and Ocean Salinity (SMOS) mission validation and the prelaunch assessment of the proposed Soil Moisture Active and Passive (SMAP) mission. During CanEx-SM10, SMOS data as well as other passive and active microwave measurements were collected by both airborne and satellite platforms. Ground-based measurements of soil (moisture, temperature, roughness, bulk density) and vegetation characteristics (leaf area index, biomass, vegetation height) were conducted close in time to the airborne and satellite acquisitions. Moreover, two ground-based in situ networks provided continuous measurements of meteorological conditions and soil moisture and soil temperature profiles. Two sites, each covering 33 km × 71 km (about two SMOS pixels) were selected in agricultural and boreal forested areas in order to provide contrasting soil and vegetation conditions. This paper describes the measurement strategy, provides an overview of the data sets, and presents preliminary results. Over the agricultural area, the airborne L-band brightness temperatures matched up well with the SMOS data (prototype 346). The radio frequency interference observed in both SMOS and the airborne L-band radiometer data exhibited spatial and temporal variability and polarization dependency. The temporal evolution of the SMOS soil moisture product (prototype 307) matched that observed with the ground data, but the absolute soil moisture estimates did not meet the accuracy requirements (0.04 m3/m3) of the SMOS mission. AMSR-E soil moisture estimates from the National Snow and Ice Data Center more closely reflected soil moisture measurements.
The Soluble Guanylate Cyclase Stimulator BAY 41-2272 Inhibits Vascular Smooth Muscle Growth through the cAMP-Dependent Protein Kinase and cGMP-Dependent Protein Kinase Pathways

Vascular smooth muscle (VSM) proliferation and migration are key components in vessel remodeling. Cyclic nucleotide signaling is protective and has long-served as a therapeutic target against undesired VSM growth. The present work analyzed the effects of the soluble guanylate cyclase (sGC) stimulator 3-(4-amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine [BAY 41-2272 (BAY)] on VSM growth, and we hypothesize that BAY has the capacity to reduce proliferation and migration via cyclic nucleotide-driven kinase signaling. Perivascular BAY postballoon injury reduced neointimal growth by ∼40% compared with vehicle controls after 2 weeks. In VSM cells, BAY (10 μM) reduced proliferation by ∼40% after 72 h and migration by ∼40% after 6 h and ∼60% after 18 h without deleterious effects on cell viability. cGMP content peaked (248×) 20 min after BAY treatment and remained elevated (140×) through 60 min; however, BAY did not affect cAMP levels compared with controls. Conventional and In-Cell Western analyses showed increases in vasodilator-stimulated phosphoprotein (VASP) phosphorylation (pVASP) at serines 239 (3×) and 157 (2×), respective markers of cGMP- and cAMP-directed protein kinases (PKG and PKA, respectively). The PKG inhibitor YGRKKRRQRRRPPLRKKKKKH peptide (DT-2) completely reversed BAY-mediated increases in pVASPSer239 and BAY-mediated inhibition of migration. In comparison, the PKA inhibitor peptide PKI further potentiated BAY-stimulated pVASPSer157 and pVASPSer239 and partially reversed the antiproliferative effects of BAY. This is the first report demonstrating the effectiveness of BAY in reducing neointimal growth with direct evidence for PKG-specific antimigratory and PKA-specific antiproliferative mechanisms. Conclusively, the sGC stimulator BAY reduces VSM growth through cGMP-dependent PKG and PKA processes, providing support for continued evaluation of its clinical utility.
Cost-effectiveness of human papillomavirus DNA testing in the United Kingdom, The Netherlands, France, and Italy.

BACKGROUND European countries with established cytology-based screening programs for cervical cancer will soon face decisions about whether to incorporate human papillomavirus (HPV) DNA testing and what strategies will be most cost-effective. We assessed the cost-effectiveness of incorporating HPV DNA testing into existing cervical cancer screening programs in the United Kingdom, The Netherlands, France, and Italy. METHODS We created a computer-based model of the natural history of cervical carcinogenesis for each using country-specific data on cervical cancer risk and compared each country's current screening policy with two new strategies: 1) cytology throughout a woman's lifetime, using HPV DNA testing as a triage strategy for equivocal cytology results ("HPV triage"), as well as 2) cytology until age 30 years and HPV DNA testing in combination with cytology in women more than 30 years of age ("combination testing"). Outcomes included reduction in lifetime cervical cancer risk, increase in life expectancy, lifetime costs, and incremental cost-effectiveness ratios, expressed as cost per year of life saved. We explored alternative protocols and conducted sensitivity analysis on key parameters of the model over a relevant range of values to identify the most cost-effective options for each country. RESULTS Both HPV DNA testing strategies, HPV triage and combination testing, were more effective than each country's status quo screening policy. Incremental cost-effectiveness ratios for HPV triage were less than $13,000 per year of life saved, whereas those for combination testing ranged from $9800 to $75,900 per year of life saved, depending on screening interval. We identified options that would be very cost-effective (i.e., cost-effectiveness ratio less than the gross domestic product per capita) in each of the four countries. CONCLUSIONS HPV DNA testing has the potential to improve health benefits at a reasonable cost compared with current screening policies in four European countries.
Preoperative technetium Tc 99m sestamibi SPECT imaging in the management of primary hyperparathyroidism in patients with concomitant multinodular goiter.

HYPOTHESIS Preoperative parathyroid and thyroid imaging using technetium Tc 99m sestamibi scintigraphy-single-photon emission computed tomography (Tc 99m MIBI SPECT) and technetium Tc 99m sodium pertechnetate, respectively, in patients with parathyroid adenomas and concomitant multinodular goiters enables the selection of those suitable for minimally invasive radio-guided surgery. DESIGN One hundred thirty patients with primary hyperparathyroidism were treated surgically during a 30-month period. Forty-one of these 130 patients had an associated multinodular goiter. All patients underwent planar and SPECT parathyroid scintigraphy using Tc 99m MIBI, and thyroid scintigraphy with technetium Tc 99m pertechnetate 2 to 5 days before surgery. On the morning of surgery each patient was reinjected with Tc 99m MIBI for intraoperative localization and validation. Minimally invasive radio-guided parathyroidectomy was performed using a handheld gamma-detection device with a thyroid probe. Removed glands were submitted for histopathologic examination for comparison with the scintigraphic results. Quantitative analysis of parathyroid activity was performed. RESULTS Minimally invasive, radioguided parathyroidectomy was successfully performed in 21 (51%) of 41 patients who had a concomitant multinodular goiter. The remaining 20 patients underwent standard neck exploratory surgery because of associated thyroid disease; 5 of them had malignant thyroid disease. Among the 41 patients planar scintigraphy correctly identified 28 adenomas (68%). Single-photon emission computed tomographic imaging identified an additional 11 adenomas for a sensitivity of 95% and a specificity of 100%. Moreover, SPECT imaging correctly identified malignant thyroid nodules in 4 of 5 patients. Technetium Tc 99m MIBI retention was noted in only 25 adenomas (61%) while the remaining adenomas demonstrated a rapid washout. The average uptake ratio of parathyroid counts to maximum thyroid activity was significantly correlated with parathyroid hormone levels before surgery (P = .04). CONCLUSIONS Our data encourage the use of preoperative SPECT imaging of parathyroid adenomas in patients who have multinodular goiters to select those suitable for minimally invasive radioguided surgery. This technique also offers important information regarding thyroid nodules that are suspicious for malignancy. The intraoperative gamma-probe technique enables the surgeon to focus his or her search, provides instant feedback regarding the progress of the operation, reduces surgical trauma and complications, and yields better cosmetic results. Patients with higher presurgical parathyroid hormone levels may especially benefit from radioguided surgery.
Localization of tubular adaptation to renal sodium loss in Gitelman syndrome.

BACKGROUND AND OBJECTIVES Gitelman syndrome (GS) is a salt-wasting tubulopathy that results from the inactivation of the human thiazide-sensitive sodium chloride cotransporter located in the distal convoluted tubule. Tubular adaptation to renal sodium loss has been described and localized in the distal tubule in experimental models of GS but not in humans with GS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The tubular adaptation to renal sodium loss is described. Osmole-free water clearance and endogenous lithium clearance with furosemide infusion are used to compare 7 patients with genetically confirmed GS and 13 control participants. RESULTS Neither endogenous lithium clearance nor osmole-free water clearance disclosed enhanced proximal fluid reabsorption in patients with GS. These patients displayed significantly lower osmole-free water clearance factored by inulin clearance (7.1 ± 1.9 versus 10.1 ± 2.2; P<0.01) and significantly lower fractional sodium reabsorption in the diluting nephron (73.2% ± 7.1% versus 86.1% ± 4.7%; P<0.005), consistent with the inactivation of the thiazide-sensitive sodium chloride cotransporter. The furosemide-induced reduction rate of fractional sodium reabsorption in the diluting segment was higher in patients with GS (75.6% ± 6.1% versus 69.9% ± 3.2%; P<0.039), suggesting that sodium reabsorption would be enhanced in the cortical part of the thick ascending limb of the loop of Henle in patients with GS. CONCLUSIONS These findings suggest that tubular adaptation to renal sodium loss in GS would be devoted to the cortical part of the thick ascending limb of the loop of Henle in humans.