julilili42/papers huggingface dataset:
How multivalent salts help proteins crystallize
2016-08-28

Knowledge of the protein structure is considered a precondition for understanding their function.Crystallography remains the most powerful tool in that context, but crystal structure determination of macromolecules is often hampered by a lack of crystals suitable for diffraction.In our work, we have studied the crystallization of human serum albumin (HSA) and bovine beta-lactoglobulin (BLG) in the presence of yttrium chloride (and other multivalent salts) to yield high quality crystals with new crystal packing.We demonstrate that trivalent salts can be used to optimize crystallization conditions for globular proteins along general physical insights.We have revealed that negatively charged proteins at neutral pH in the presence of trivalent salts undergo a "reentrant condensation" phase behavior [1-3], i.e. a phase-separated regime occurs in between two critical salt concentrations, c* < c**, giving rise to a metastable liquid-liquid phase separation (LLPS) [3,4].Crystallization from the condensed regime follows different mechanisms.Near c*, crystals grow following a classic nucleation and growth mechanism; near LLPS binodal, crystallization follows a two-step mechanism, i.e, crystals growth follows a metastable LLPS [4][5][6][7][8].The yttrium ions are not only used to engineer crystallization, but are an integral part of the crystal lattice and can therefore be used to solve the phase problem using anomalous dispersion methods.The structure analysis demonstrates the specific binding of yttrium ions to surface-exposed glutamate and aspartate side chains contributed by different molecules in the crystal lattice.By bridging molecules in this manner, contacts between molecules are formed that enable the formation of a stable crystal lattice.Based on this bridging effect, an ion-activated patchy colloidal model was proposed to rationalize the phase behaviour observed experimentally [9].
FOXP2 variants in 14 individuals with developmental speech and language disorders broaden the mutational and clinical spectrum
2016-08-29

Background Disruptions of the FOXP2 gene, encoding a forkhead transcription factor, are the first known monogenic cause of a speech and language disorder. So far, mainly chromosomal rearrangements such as translocations or larger deletions affecting FOXP2 have been reported. Intragenic deletions or convincingly pathogenic point mutations in FOXP2 have up to date only been reported in three families. We thus aimed at a further characterisation of the mutational and clinical spectrum. Methods Chromosomal microarray testing, trio exome sequencing, multigene panel sequencing and targeted sequencing of FOXP2 were performed in individuals with variable developmental disorders, and speech and language deficits. Results We identified four different truncating mutations, two novel missense mutations within the forkhead domain and an intragenic deletion in FOXP2 in 14 individuals from eight unrelated families. Mutations occurred de novo in four families and were inherited from an affected parent in the other four. All index patients presented with various manifestations of language and speech impairment. Apart from two individuals with normal onset of speech, age of first words was between 4 and 7 years. Articulation difficulties such as slurred speech, dyspraxia, stuttering and poor pronunciation were frequently noted. Motor development was normal or only mildly delayed. Mild cognitive impairment was reported for most individuals. Conclusions By identifying intragenic deletions or mutations in 14 individuals from eight unrelated families with variable developmental delay/cognitive impairment and speech and language deficits, we considerably broaden the mutational and clinical spectrum associated with aberrations in FOXP2 .
Bayesian Model Selection Helps To Choose Objectively between Thermodynamic Models: A Demonstration of Selecting a Viscosity Model Based on Entropy Scaling
2016-08-29

Objective measures to compare the adequacy of models can be very useful to guide the development of thermodynamic models. Thermodynamicists are frequently faced with the so-called bias-variance dilemma, where one model may be less accurate in correlating experimental data but more robust in extrapolations than another model. In this work, we use Bayesian model selection (BMS) to identify the optimal balance between bias and variance. BMS is a statistically rigorous procedure that elegantly accounts for experimental errors and implicitly performs a bias-variance tradeoff in model selection. We present a first-time application of BMS to thermodynamic model selection. As an example, we consider modeling approaches to predict viscosities using Rosenfeld's entropy scaling approach [Y. Rosenfeld, Phys. Rev. A 1977, 15, 2545–2549]. Our goal is to objectively rank the adequacy of three competing model variants that all describe the functional dependence of viscosity on residual entropy: the well-established linear regression approach, a recently introduced polynomial approach [O. Lötgering-Lin, J. Gross, Ind. Eng. Chem. Res. 2015, 54, 7942–7952], and a sinusoidal approach. We investigate the suitability of the models for extrapolating viscosities to different pressures and to different carbon chain lengths. Technically, we implement, in a first step, a Markov chain Monte Carlo algorithm to train the competing models on a common dataset. In a second step, we determine the statistical evidence for each model in light of an evaluation dataset with brute-force Monte Carlo integration. We call this method of implementation "two-step BMS". Results show that, generally, both nonlinear models outperform the linear model, with the polynomial approach being much more reliable for carbon chain length extrapolation. However, assumptions about experimental error influence the choice of the most appropriate model candidate. Hence, we point out the benefits of applying two-step BMS based on specific datasets and specific error assumptions as a situation-specific guide to model selection.
A High-CoverageYersinia pestisGenome from a Sixth-Century Justinianic Plague Victim
2016-08-30

The Justinianic Plague, which started in the sixth century and lasted to the mid eighth century, is thought to be the first of three historically documented plague pandemics causing massive casualties. Historical accounts and molecular data suggest the bacterium Yersinia pestis as its etiological agent. Here we present a new high-coverage (17.9-fold) Y. pestis genome obtained from a sixth-century skeleton recovered from a southern German burial site close to Munich. The reconstructed genome enabled the detection of 30 unique substitutions as well as structural differences that have not been previously described. We report indels affecting a lacl family transcription regulator gene as well as nonsynonymous substitutions in the nrdE, fadJ, and pcp genes, that have been suggested as plague virulence determinants or have been shown to be upregulated in different models of plague infection. In addition, we identify 19 false positive substitutions in a previously published lower-coverage Y. pestis genome from another archaeological site of the same time period and geographical region that is otherwise genetically identical to the high-coverage genome sequence reported here, suggesting low-genetic diversity of the plague during the sixth century in rural southern Germany.
Competing for Iron: Duplication and Amplification of the isd Locus in Staphylococcus lugdunensis HKU09-01 Provides a Competitive Advantage to Overcome Nutritional Limitation
2016-08-30

Staphylococcus lugdunensis is a coagulase negative bacterial pathogen that is particularly associated with severe cases of infectious endocarditis. Unique amongst the coagulase-negative staphylococci, S. lugdunensis harbors an iron regulated surface determinant locus (isd). This locus facilitates the acquisition of heme as a source of nutrient iron during infection and allows iron limitation caused by "nutritional immunity" to be overcome. The isd locus is duplicated in S. lugdunensis HKU09-01 and we show here that the duplication is intrinsically unstable and undergoes accordion-like amplification and segregation leading to extensive isd copy number variation. Amplification of the locus increased the level of expression of Isd proteins and improved binding of hemoglobin to the cell surface of S. lugdunensis. Furthermore, Isd overexpression provided an advantage when strains were competing for a limited amount of hemoglobin as the sole source of iron. Gene duplications and amplifications (GDA) are events of fundamental importance for bacterial evolution and are frequently associated with antibiotic resistance in many species. As such, GDAs are regarded as evolutionary adaptions to novel selective pressures in hostile environments pointing towards a special importance of isd for S. lugdunensis. For the first time we show an example of a GDA that involves a virulence factor of a Gram-positive pathogen and link the GDA directly to a competitive advantage when the bacteria were struggling with selective pressures mimicking "nutritional immunity".
Magnetoelectric spectroscopy of Andreev bound states in Josephson quantum dots
2016-08-30

We theoretically investigate the behavior of Andreev levels in a\\nsingle-orbital interacting quantum dot in contact to superconducting leads,\\nfocusing on the effect of electrostatic gating and applied magnetic field, as\\nrelevant for recent experimental spectroscopic studies. In order to account\\nreliably for spin-polarization effects in presence of correlations, we extend\\nhere two simple and complementary approaches that are tailored to capture\\neffective Andreev levels: the static functional renormalization group (fRG) and\\nthe self-consistent Andreev bound states (SCABS) theory. We provide benchmarks\\nagainst the exact large-gap solution as well as NRG calculations and find good\\nquantitative agreement in the range of validity. The large flexibility of the\\nimplemented approaches then allows us to analyze a sizeable parameter space,\\nallowing to get a deeper physical understanding into the Zeeman field,\\nelectrostatic gate, and flux dependence of Andreev levels in interacting\\nnanostructures.\\n
Tofacitinib and Analogs as Inhibitors of the Histone Kinase Prk1 (Pkn1)
2016-08-30

The identified inhibitors and the selectivity hotspots lay the basis for the development of selective PRK1 inhibitors. The identification of PRK1, but also of other cellular tofacitinib targets, has implications on its clinical use and on future development of tofacitinib-like JAK inhibitors. [Formula: see text].
Assessing the reproducibility of high definition urethral pressure profilometry and its correlation with an air‐charged system
2016-08-30

Introduction Recently, a new urodynamic method for the assessment of stress urinary incontinence called high definition urethral pressure profilometry (HD‐UPP) has been introduced. This method combines a novel microtip catheter with advanced signal processing to enable spatial data location and the reconstruction of a pressure image inside the urethra. In order to assess the reproducibility of HD‐UPP data, we statistically evaluate HD‐UPP datasets and compare them to data from a double balloon air‐charged system. Materials and Methods Both catheters are used on sedated female minipigs. Data from the microtip catheter are processed through a signal reconstruction algorithm, urodynamic features are extracted, and compared to the air‐charged system. Reproducibility of HD‐UPP data is assessed by statistically evaluating consecutive, intra‐individual datasets. Results HD‐UPP delivers results in agreement with previous comparisons of microtip and air‐charged systems. The average deviation of two consecutive, intra‐individual pressure images is very low at 7 cm H 2 O. Conclusions HD‐UPP provides physicians with detailed information on the pressure distribution inside the urethra. Through comparison with an air‐charged catheter, it is shown that HD‐UPP delivers results in agreement with previous studies on the comparison of microtip and air‐charged catheters. It provides excellent reproducibility, as the difference between sequentially measured profiles from the same minipig is significantly lower than the one between profiles from different minipigs.
Synthesis and NMR studies of malonyl-linked glycoconjugates of N-(2-aminoethyl)glycine. Building blocks for the construction of combinatorial glycopeptide libraries
2016-08-30

Four glycoconjugate building blocks for the construction of combinatorial PNA like glycopeptide libraries were prepared in 75–79% yield by condensing tert -butyl N -[2-( N -9-fluorenylmethoxycarbonylamino)ethyl]glycinate (AEG) 5 with 3-oxo-3-(2,3,4,6-tetra- O -acetyl-β-D-glucopyranosylamino)- ( 6a ), 3-oxo-3-(β-D-galactopyranosylamino)- ( 6b ), 3-oxo-3-(2-acetamido-2-deoxy-3,4,6-tetra- O -acetyl-β-D-glucopyranosylamino)- ( 6c ) and 3-oxo-3-(2-acetamido-2-deoxy-3,4,6-tetra- O -acetyl-β-D-galactopyranosylamino)propanoic acid ( 6d) , respectively. The resulting AEG glycoconjugates 1a–d were converted into the corresponding free acids 2a–d in 97–98% yield by treatment with aqueous formic acid. The Fmoc group of compound 1c was removed and the intermediate amine 9 was condensed with 2a to afford the corresponding glycosylated AEG dipeptide 4 in 58% yield. All glycoconjugate building blocks showed the presence of cis and trans rotamers. Compounds 1a , 1b and 4 were subjected to temperature dependent 1 H NMR spectroscopy in order to determine the coalescence temperature which resulted in calculated rotation barriers of 17.9–18.3 kcal/mol for the rotamers.
Computer assisted evaluation of plate osteosynthesis of diaphyseal femur fracture considering interfragmentary movement: a finite element study
2016-08-30

Abstract A semi-automated workflow for evaluation of diaphyseal fracture treatment of the femur has been developed and implemented. The aim was to investigate the influence of locking compression plating with diverse fracture-specific screw configurations on interfragmentary movements (IFMs) with the use of finite element (FE) analysis. Computed tomography (CT) data of a 22-year-old non-osteoporotic female were used for patient specific modeling of the inhomogeneous material properties of bone. Hounsfield units (HU) were exported and assigned to elements of a FE mesh and converted to mechanical properties such as the Young’s modulus followed by a linear FE analysis performed in a semi-automated fashion. IFM on the near and far cortex was evaluated. A positive correlation between bridging length and IFM was observed. Optimal healing conditions with IFMs between 0.5 mm and 1 mm were found in a constellation with a medium bridging length of 80 mm with three unoccupied screw holes around the fracture gap. Usage of monocortical screws instead of bicortical ones had negligible influence on the evaluated parameters when modeling non-osteoporotic bone. Minimal user input, automation of the procedure and an efficient computation time ensured quick delivery of results which will be essential in a future clinical application.
2016-08-30

Aims. We present the results of the monitoring programmes performed with the Swift/XRT telescope and aimed specifically to detect an abrupt decrease of the observed flux associated with a transition to the propeller regime in two well-known X-ray pulsars 4U 0115+63 and V 0332+53. Methods. Both sources form binary systems with Be optical companions and undergo so-called giant outbursts every 3−4 years. The current observational campaigns were performed with the Swift/XRT telescope in the soft X-ray band (0.5−10 keV) during the declining phases of the outbursts exhibited by both sources in 2015. Results. The transitions to the propeller regime were detected at the threshold luminosities of (1.4 ± 0.4) × 1036 erg s-1 and (2.0 ± 0.4) × 1036 erg s-1 for 4U 0115+63 and V 0332+53, respectively. Spectra of the sources are shown to be significantly softer during the low state. In both sources, the accretion at rates close to the aforementioned threshold values briefly resumes during the periastron passage following the transition into the propeller regime. The strength of the dipole component of the magnetic field required to inhibit the accretion agrees well with estimates based on the position of the cyclotron lines in their spectra, thus excluding presence of a strong multipole component of the magnetic field in the vicinity of the neutron star.
P. SHAW (ED.), THE ETERNAL LETTER: TWO MILLENNIA OF THE CLASSICAL ROMAN CAPITAL (Codex Studies in Letterforms). Cambridge, MA: MIT Press, 2015. Pp. viii + 258, illus. isbn 9780262029018. £37.95/US$55.00.
2016-08-30

P. SHAW (ED.), THE ETERNAL LETTER: TWO MILLENNIA OF THE CLASSICAL ROMAN CAPITAL (Codex Studies in Letterforms). Cambridge, MA: MIT Press, 2015. Pp. viii + 258, illus. isbn 9780262029018. £37.95/US$55.00. - Volume 106
Clinicopathological Features and Prognostic Value of Incidental Prostatic Adenocarcinoma in Radical Cystoprostatectomy Specimens: A Systematic Review and Meta-Analysis of 13,140 Patients
2016-08-31

This meta-analysis suggests that incidental prostate cancer detected during histopathological examination of radical cystoprostatectomy specimens might be linked with adverse characteristics and outcomes in patients with invasive bladder cancer.
Novel epi-virotherapeutic treatment of pancreatic cancer combining the oral histone deacetylase inhibitor resminostat with oncolytic measles vaccine virus
2016-08-31

Oncolytic viruses (OV) constitute highly promising innovative biological anticancer agents. However, like every other antitumoral compound, OV are also faced with both primary and secondary mechanisms of resistance. To overcome those barriers and moreover amplify the therapeutic potential of OV, we evaluated a novel combined approach composed of the oral histone deacetylase inhibitor resminostat and an oncolytic measles vaccine virus (MeV) for a future epi‐virotherapy of pancreatic ductal adenocarcinoma. Cytotoxicity assays revealed that combined epi-virotherapeutic treatment of four well-characterized human pancreatic cancer cell lines resulted in a beneficial tumor cell killing as compared to either monotherapeutic approach. Notably, epi-virotherapeutic treatment of MIA PaCa-2 and partly also of PANC‐1 pancreatic cancer cells resulted in a tumor cell mass reduction being significantly more pronounced than it would be expected in case of an additive effect only, indicating a synergistic mode of action when combining resminostat with MeV. We further found that the epigenetic compound resminostat neither impaired MeV growth kinetics nor prevented the activation of the interferon signaling pathway which plays an important role in mediating primary and secondary resistances to OV. Moreover, we yielded information that the pharma-codynamic function of resminostat was presumably not altered in the course of pancreatic cancer cell infections with MeV. Taken together, these promising results favor the onset of epi-viro-thera-peutic clinical trials in patients suffering from advanced pancreatic ductal adenocarcinoma.
The Role of Prefrontal Mixed Selectivity in Cognitive Control
2016-08-31

Cognitive control is the ability to modify responses to a given stimulus according to changing contexts or goals ([Miller and Cohen, 2001][1]). It encompasses diverse functions, including working memory, attention, context and goal processing, and response inhibition. Given the multifaceted nature
A Neural Algorithm of Artistic Style
2016-09-01

In fine art, especially painting, humans have mastered the skill to create unique visual experiences through composing a complex interplay between the content and style of an image. Thus far the algorithmic basis of this process is unknown and there exists no artificial system with similar capabilities. However, in other key areas of visual perception such as object and face recognition near-human performance was recently demonstrated by a class of biologically inspired vision models called Deep Neural Networks. Here we introduce an artificial system based on a Deep Neural Network that creates artistic images of high perceptual quality. The system uses neural representations to separate and recombine content and style of arbitrary images, providing a neural algorithm for the creation of artistic images. Moreover, in light of the striking similarities between performance-optimised artificial neural networks and biological vision, our work offers a path forward to an algorithmic understanding of how humans create and perceive artistic imagery.
Peripheral blood myeloid-derived suppressor cells reflect disease status in idiopathic pulmonary fibrosis
2016-09-01

Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative disease with irreversible lung function loss and poor survival. Myeloid-derived suppressor cells (MDSC) are associated with poor prognosis in cancer, facilitating immune evasion. The abundance and function of MDSC in IPF is currently unknown. Fluorescence-activated cell sorting was performed in 170 patients (IPF: n=69; non-IPF interstitial lung disease (ILD): n=56; chronic obstructive pulmonary disease (COPD): n=23; healthy controls: n=22) to quantify blood MDSC and lymphocyte subtypes. MDSC abundance was correlated with lung function, MDSC localisation was performed by immunofluorescence. Peripheral blood mononuclear cell (PBMC) mRNA levels were analysed by qRT-PCR. We detected increased MDSC in IPF and non-IPF ILD compared with controls (30.99±15.61% versus 18.96±8.17%, p≤0.01). Circulating MDSC inversely correlated with maximum vital capacity (r= −0.48, p≤0.0001) in IPF, but not in COPD or non-IPF ILD. MDSC suppressed autologous T-cells. The mRNA levels of co-stimulatory T-cell signals were significantly downregulated in IPF PBMC. Importantly, CD33 + CD11b + cells, suggestive of MDSC, were detected in fibrotic niches of IPF lungs. We identified increased MDSC in IPF and non-IPF ILD, suggesting that elevated MDSC may cause a blunted immune response. MDSC inversely correlate with lung function only in IPF, identifying them as potent biomarkers for disease progression. Controlling expansion and accumulation of MDSC, or blocking their T-cell suppression, represents a promising therapy in IPF.