Miracle-dz/UniFAR-FTUs huggingface dataset:
Fast Multi-blind Modification Search through Tandem Mass Spectrometry*

With great biological interest in post-translational modifications (PTMs), various approaches have been introduced to identify PTMs using MS/MS. Recent developments for PTM identification have focused on an unrestrictive approach that searches MS/MS spectra for all known and possibly even unknown types of PTMs at once. However, the resulting expanded search space requires much longer search time and also increases the number of false positives (incorrect identifications) and false negatives (missed true identifications), thus creating a bottleneck in high throughput analysis. Here we introduce MODa, a novel “multi-blind” spectral alignment algorithm that allows for fast unrestrictive PTM searches with no limitation on the number of modifications per peptide while featuring over an order of magnitude speedup in relation to existing approaches. We demonstrate the sensitivity of MODa on human shotgun proteomics data where it reveals multiple mutations, a wide range of modifications (including glycosylation), and evidence for several putative novel modifications. Based on the reported findings, we argue that the efficiency and sensitivity of MODa make it the first unrestrictive search tool with the potential to fully replace conventional restrictive identification of proteomics mass spectrometry data.
Stability of Networked Control Systems Under a Multiple-Packet Transmission Policy

This paper is concerned with stability analysis of discrete-time networked control systems subject to packet loss under a multiple-packet transmission policy with the packet dropping probability of the communication channel bounded from above. Necessary and sufficient conditions for stability are obtained. In addition, the packet dropping margin as a measure of stability robustness of a system against packet loss is defined and its formula is derived. A design method is proposed for enhancing stability robustness subject to the constraint of a set of prescribed nominal closed-loop poles.
Structure and Function of Human Xylulokinase, an Enzyme with Important Roles in Carbohydrate Metabolism*

Background: d-Xylulokinase (XK), the final enzyme in the glucuronate-xylulose pathway, produces a key regulator of lipogenesis, xylulose 5-phosphate. Results: The structure of human XK was determined, and its catalytic activity and inhibition were characterized. Conclusion: Human XK is selective for d-xylulose and is inhibited by 5-deoxy-5-fluoro-d-xylulose. Significance: Inhibition of XK could clarify its roles in sugar metabolism, lipogenesis, and metabolic disease. d-Xylulokinase (XK; EC 2.7.1.17) catalyzes the ATP-dependent phosphorylation of d-xylulose (Xu) to produce xylulose 5-phosphate (Xu5P). In mammals, XK is the last enzyme in the glucuronate-xylulose pathway, active in the liver and kidneys, and is linked through its product Xu5P to the pentose-phosphate pathway. XK may play an important role in metabolic disease, given that Xu5P is a key regulator of glucose metabolism and lipogenesis. We have expressed the product of a putative human XK gene and identified it as the authentic human d-xylulokinase (hXK). NMR studies with a variety of sugars showed that hXK acts only on d-xylulose, and a coupled photometric assay established its key kinetic parameters as Km(Xu) = 24 ± 3 μm and kcat = 35 ± 5 s−1. Crystal structures were determined for hXK, on its own and in complexes with Xu, ADP, and a fluorinated inhibitor. These reveal that hXK has a two-domain fold characteristic of the sugar kinase/hsp70/actin superfamily, with glycerol kinase as its closest relative. Xu binds to domain-I and ADP to domain-II, but in this open form of hXK they are 10 Å apart, implying that a large scale conformational change is required for catalysis. Xu binds in its linear keto-form, sandwiched between a Trp side chain and polar side chains that provide exquisite hydrogen bonding recognition. The hXK structure provides a basis for the design of specific inhibitors with which to probe its roles in sugar metabolism and metabolic disease.
3D high temporal and spatial resolution contrast‐enhanced MR angiography of the whole brain

Sensitivity encoding (SENSE) and partial Fourier techniques have been shown to reduce the acquisition time and provide high diagnostic quality images. However, for time‐resolved acquisitions there is a need for both high temporal and spatial resolution. View sharing can be used to provide an increased frame rate but at the cost of acquiring spatial frequencies over a duration longer than a frame time. In this work we hypothesize that a CArtesian Projection Reconstruction‐like (CAPR) technique in combination with 2D SENSE, partial Fourier, and view sharing can provide 1–2 mm isotropic resolution with sufficient temporal resolution to distinguish intracranial arterial and venous phases of contrast passage in whole‐brain angiography. In doing so, the parameter of “temporal footprint” is introduced as a descriptor for characterizing and comparing time‐resolved view‐shared pulse sequences. It is further hypothesized that short temporal footprint sequences have higher temporal fidelity than similar sequences with longer temporal footprints. The tradeoff of temporal footprint and temporal acceleration is presented and characterized in numerical simulations. Results from 11 whole‐brain contrast‐enhanced MR angiography studies with the new method with SENSE acceleration factors R = 4 and 5.3 are shown to provide images of comparable or higher diagnostic quality than the unaccelerated reference. Magn Reson Med 60:749–760, 2008. © 2008 Wiley‐Liss, Inc.
10p11.2 to 10q11.2 is a yet unreported region leading to unbalanced chromosomal abnormalities without phenotypic consequences

Directly transmitted unbalanced chromosomal abnormalities (UBCA) or euchromatic variants (EV) were recently reported for >50 euchromatic regions of almost all human autosomes. UBCA and EV are comprised of a few megabases of DNA, and carriers are in many cases clinically healthy. Here we report on partial trisomies of chromosome 10 within the pericentromeric region which were detected by standard G banding. Those were referred for further delineation of the size of these duplicated regions for molecular cytogenetics and/or array-CGH. Partial trisomies of chromosome 10 in the pericentromeric region were identified prenatally in seven cases. A maximum of three copies of the region from 10p12.1 to 10q11.22 was observed in all cases without apparent clinical abnormalities. The imbalances were either caused by a direct duplication in one familial case or by de novo small supernumerary marker chromosomes (sSMC). Thus, we report a yet unrecognized chromosomal region subject to UBCA detected in seven unrelated cases. To the best of our knowledge, this is the first report of a UBCA in the pericentromeric region of chromosome 10 that is not correlated with any clinical consequences.
Fully aligned via integration for extendibility of interconnects to beyond the 7 nm node

A fully aligned via (FAV) integration scheme is introduced and demonstrated at 36 nm metal pitch, with extendibility to beyond the 7 nm node. Selective chemistries were developed to recess Cu and W wires and their associated barrier liner materials, so as to create local topography with no adverse effects on these wiring levels or their dielectrics. Dielectric cap layers were optimized for excellent via RIE selectivity, to act as via guiding structures during subsequent level pattern definition. This combination mitigates via overlay and critical dimension (CD) errors. FAV integration can enable line/via area scaling for 70% lower line resistances and 30% larger via contact areas at the same node. Concurrently, FAV improves TDDB reliability through increased minimum insulator spacing, and EM reliability by maximizing via/wire contact area.
Computational diagnosis of protein conformational diseases: Short molecular dynamics simulations reveal a fast unfolding of r‐LDL mutants that cause familial hypercholesterolemia

The molecular basis of conformational diseases frequently resides in mutant proteins constituting a subset of the vast mutational space. While the subtleties of protein structure point to molecular dynamics (MD) techniques as promising tools for an efficient exploration of such a space, the average size of proteins and the time scale of unfolding events make this goal difficult with present computational capabilities. We show here, nevertheless, that an efficient approach is already feasible for modular proteins. Familial hypercholesterolemia (FH) is a conformational disease linked to mutations in the gene encoding the low density lipoprotein receptor. A high percentage of these mutations has been found in the seven small modular binding repeats of the receptor. Taking advantage of its small size, we have performed an in depth MD study of the fifth binding repeat. Fast unfolding dynamics have been observed in the absence of a structural bound calcium ion, which agrees with its reported essential role in the stability of the module. In addition, several mutations detected in FH patients have been analyzed, starting from the native conformation. Our results indicate that in contrast with the wild type protein and an innocuous control mutant, disease‐related mutants experience, in short simulation times (2–8 ns), gross departures from the native state that lead to unfolded conformations and, in some cases, to binding site desorganization deriving in calcium release. Computational diagnosis of mutations leading to conformational diseases seems thus feasible, at least for small or modular pathogenic proteins. Proteins 2007. © 2006 Wiley‐Liss, Inc.
Ambient temperature and sexual activity: Evidence from time use surveys

BACKGROUND Previous research has found that unusually hot temperatures reduce birth rates eight to ten months later. OBJECTIVE We examine one of the potential mechanisms behind this relationship: the connection between ambient temperature and sexual activity. METHODS We use individual-level data provided by three waves of the Hungarian Time Use Survey between 1986 and 2010 and daily weather data from the European Climate Assessment & Dataset project. RESULTS Hot temperatures do not have a significant effect on sexual activity on a given day. Studying the dynamics of the relationship, we found that temperature does not influence sexual activity on subsequent days either. CONCLUSIONS Since high temperatures seem to have no negative effect on sexual activity, the relationship between temperature and sexual activity might be a mechanism of minor importance in the relationship between temperature and birth rates. CONTRIBUTION Our paper is the first study of the relationship between ambient temperature and sexual activity that uses time use data. 1 Institute of Economics, Centre for Economic and Regional Studies, Hungarian Academy of Sciences, Budapest, Hungary. Email: hajdu.tamas@krtk.mta. hu. 2 Institute for Sociology, Centre for Social Sciences, Hungarian Academy of Sciences, Budapest, Hungary; MTA-ELTE Peripato Comparative Social Dynamics Research Group, Budapest, Hungary. Hajdu & Hajdu: Ambient temperature and sexual activity: Evidence from time use surveys 308 http://www.demographic-research.org
Machine Learned Learning Machines

There are two common approaches for optimizing the performance of a machine: genetic algorithms and machine learning. A genetic algorithm is applied over many generations whereas machine learning works by applying feedback until the system meets a performance threshold. Though these are methods that typically operate separately, we combine evolutionary adaptation and machine learning into one approach. Our focus is on machines that can learn during their lifetime, but instead of equipping them with a machine learning algorithm we aim to let them evolve their ability to learn by themselves. We use evolvable networks of probabilistic and deterministic logic gates, known as Markov Brains, as our computational model organism. The ability of Markov Brains to learn is augmented by a novel adaptive component that can change its computational behavior based on feedback. We show that Markov Brains can indeed evolve to incorporate these feedback gates to improve their adaptability to variable environments. By combining these two methods, we now also implemented a computational model that can be used to study the evolution of learning.
Quantitation of Plasma Membrane Expression of a Fusion Protein of Na/H Exchanger NHE3 and Green Fluorescence Protein (GFP) in Living PS120 Fibroblasts

We developed a confocal morphometric analysis to quantitate the relative plasma membrane (PM) expression of the Na/H exchanger NHE3 in living PS120 fibroblasts. NHE3 is a membrane transport protein that is acutely regulated by changes in the number of molecules expressed at the PM. To quantitate the PM expression of NHE3 under various experimental conditions, we stably expressed a chimera of rabbit NHE3 and green fluorescent protein (NHE3–GFP) in PS120 fibroblasts. A three-dimensional (3D) map of the intracellular distribution of NHE3–GFP was obtained by confocal laser scanning microscopy (CLSM) of cells superfused with a styryl dye, FM 4–64. This fluorophore rapidly and reversibly labeled the outer lipid layer of the PM, which allowed generation of a digital mask of the PM and calculation of the fraction of a total cellular NHE3–GFP expressed at the PM. This analysis was successfully used to quantitate the relative PM expression of NHE3–GFP in control cells (25%) and a decrease in the expression caused by subsequent exposure of cells to wortmannin (5.1%). Reliability of the method was confirmed by cell surface biotinylation, which yielded very similar results. Confocal morphometric analysis is fast and reproducible and could potentially be used for investigations on regulation of expression of other membrane proteins.
Protein engineering of insulin: Two novel fast-acting insulins [B16Ala]insulin and [B26Ala]insulin

Blood glucose lowering assay proved that [B16Ala]insulin and [B26Ala]insulin exhibit potency of acute blood glucose lowering in normal pigs, which demonstrates that they are fastacting insulin. Single-chain precursor of [B16Ala]insulin and [B26Ala]insulin is [B16Ala]PIP and [B26Ala]PIP, respectively, which are suitable for gene expression. Secretory expression level of the precursors in methylotrophic yeast Pichia pastoris was quite high, 650 mg/L and 130 mg/L, respectively. In vivo biological assay showed that the two fast-acting insulins have full or nearly full biological activity. So both [B16Ala]insulin and [B26Ala]insulin can be well developed as fast-acting insulin for clinic use.
Effect of Armature Reaction of a Permanent-Magnet Claw Pole SMC Motor

The finite-element method enables an accurate analysis for the study on effects of armature reaction in electromagnetic devices, particularly those with complex structures and three-dimensional (3-D) magnetic flux paths. This paper investigates the effects of armature reaction on the parameters and performance of a permanent-magnet (PM) claw pole motor with soft magnetic composite (SMC) core, based on the magnetic field analysis using the 3-D nonlinear time-stepping finite-element method. The current in the stator winding produces a magnetic field, which interacts with the air gap field generated by the rotor magnets. Consequently, the air gap flux density profile against the rotor position produced by the rotor magnets deviates, and so does the back electromotive force. Since the stator field also changes the local saturation level of the magnetic core, the winding inductance varies with both the rotor position and stator currents. The inclusion of these effects in terms of parameter variations in the motor model is important for accurate performance analysis. On the other hand, the pattern of inductance against the rotor position and stator currents can be employed to effectively predict the rotor position at standstill and low speeds for robust sensorless control. The parameter computations are verified by experimental results on the PM claw pole SMC motor prototype
The induction and suppression of the apoptotic response of HSV-1 in human corneal epithelial cells.

PURPOSE HSV-1 has been shown to block apoptosis in some cell lines when the cells are exposed to exogenous agents (e.g., sorbitol). The purpose of this study was to determine whether HSV-1 infection of human corneal epithelial (HCE) cells alone induces an early proapoptotic response and whether this response is subsequently downregulated during the infection. METHODS HCE cells were infected with HSV-1 or subjected to osmotic shock (sorbitol). Fluorescent staining for annexin V binding, mitochondrial membrane potential, and DNA condensation and assays for caspase 8, 9, and 3 activity and cytokeratin 18 cleavage were performed, to assess the apoptotic pathway. RESULTS HSV-1 infection of HCE cells induced a rapid proapoptotic response, characterized by translocation of phosphatidylserine to the external membrane, activation of caspases 8 and 3 within 2 hours, and cleavage of cytokeratin 18. However, the induced response was downregulated during the infection, and later stages of the apoptotic responses (e.g., DNA condensation) were not produced. Sorbitol treatment led to terminal apoptosis by 12 hours, as indicated by DNA condensation of treated cells and reduction in the number of viable cells. CONCLUSIONS HSV-1 can induce and subsequently suppress the apoptotic pathway in HCE. Suppression of apoptosis occurred only during HSV-1 infection and not after treatment with sorbitol, suggesting that the suppression of apoptosis may be a mechanism of viral survival.
Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease.

STUDY OBJECTIVES To assess the efficacy and safety of continuous subcutaneous infusion of treprostinil, a stable prostacyclin analogue, for treating pulmonary arterial hypertension (PAH) in patients with connective tissue disease (CTD). DESIGN Two multicenter, randomized, double-blind, placebo-controlled, prospective trials of treprostinil vs placebo in 470 patients with PAH. PATIENTS A subset of 90 patients with PAH and CTD, including systemic lupus erythematosus, diffuse scleroderma, limited scleroderma, and mixed CTD/overlap syndrome. INTERVENTIONS Patients received either treprostinil (initiated at 1.25 ng/kg/min, and titrated upward) or placebo via continuous subcutaneous infusion. The maximum dose of treprostinil allowed was 22.5 ng/kg/min. MEASUREMENTS Six-minute walk (6MW) distance and dyspnea-fatigue scores were determined at baseline, and at 6 weeks and 12 weeks. Hemodynamic measures were obtained at baseline and at 12 weeks. RESULTS At baseline, most patients had New York Heart Association class III symptoms. The mean baseline 6MW distance was 289 m (range, 60 to 448 m). The mean dose of treprostinil at week 12 was 8.4 ng/kg/min (range, 1.25 to 17.5 ng/kg/min). After 12 weeks, the change in cardiac index from baseline was + 0.2 +/- 0.08 L/min/m(2) in the treprostinil group and - 0.07 +/- 0.07 L/min/m(2) in the placebo group (p = 0.007). The pulmonary vascular resistance index decreased by 4 +/- 2 U x m(2) in the treprostinil group and increased by 1 +/- 1 U x m(2) in the placebo group (p = 0.006). The placebo-corrected median improvement from baseline in 6MW distance was 25 m in treprostinil-treated patients (p = 0.055); this improvement appeared to be dose related. Dyspnea fatigue scores also improved in the treprostinil group compared with the placebo group (p = 0.014). Adverse events included infusion site pain and typical side effects related to prostaglandins, and were tolerated by most patients. CONCLUSIONS Continuous subcutaneous infusion of treprostinil in patients with PAH associated with CTD improved exercise capacity, symptoms of PAH, and hemodynamics.
Vessel formation by choroidal endothelial cells in vitro is modulated by retinal pigment epithelial cells.

OBJECTIVE To elucidate the mechanism of bovine choroidal endothelial (BCE) cell angiogenesis and, in particular, the role of retinal pigment epithelial (RPE) cells by use of an in vitro coculture assay system. METHODS The BCE cells were isolated from choroidal tissues and cultured. They were embedded in type I collagen gel and incubated. The gel-embedded BCE cells were then covered with a monolayer of RPE cells, pericytes, choroidal fibroblasts, or additional BCE cells on culture day 0 or day 14. The BCE cells in culture formed a meshwork of tubelike structures. The length of the tubelike structures (micrometers per field) was quantified by image analysis, as an indicator of angiogenesis. The effect of RPE cells on normal and growth-arrested BCE cell tube formation was evaluated in this assay system. The mechanism of RPE-induced angiogenesis was studied by parallel experiments with the use of neutralizing antibodies against specific growth factors (basic fibroblast growth factor, vascular endothelial growth factor, and transforming growth factor beta). RESULTS Ultrastructural analysis revealed that the tubelike structures had features typical of choroidal endothelial cells. Cocultures initiated on day 0 revealed that BCE cell angiogenesis was promoted by overlying RPE cells and, to a lesser extent, by pericytes, choroidal fibroblasts, and additional BCE cells when compared with BCE cells without covering cells. In cocultures initiated after BCE tube formation (day 14), there was inhibition of BCE angiogenesis by overlying RPE cells when compared with cultures without overlay or with an overlay of BCE cells. The RPE cells stimulated tube formation of growth-arrested BCE cells less effectively than did normal BCE cells. Neutralizing antibody for basic fibroblast growth factor and vascular endothelial growth factor, but not transforming growth factor beta, inhibited control and RPE-induced tube formation by BCE cells. CONCLUSIONS Overlying RPE cells stimulate the formation of tubelike structures by choroidal endothelial cells more effectively than do fibroblasts or pericytes but inhibit BCE tube formation in older cultures. The effect involves endothelial proliferation and differentiation. The stimulatory effect of overlying RPE cells can be inhibited by neutralizing antibodies to vascular endothelial growth factor and basic fibroblast growth factor, which suggests that these growth factors play an important role in this phenomenon.
Modelling the asymmetric responses of price level to oil price changes in Qatar

ABSTRACT This paper inspects the asymmetric effect of oil price on prices level in Qatar. To achieve that, we proceed by employing a nonlinear autoregressive distributed lag (ARDL) approach on data during the period 1990Q1–2014Q4. The estimation results show evidences of an incomplete and asymmetric influence of oil price on price level in the long term. Moreover, we find that price responses to negative changes in oil price is greater than its response to positive changes. Given Qatar’s economic features, a decrease in oil price could cause lower imports and production prices and consequently a substantial influence on domestic prices level. However, the lower effect of positive oil price changes on consumer prices can be explained by the subsidies system, the consumption patterns, and the exchange rate regime.