Miracle-dz/UniFAR-FTUs huggingface dataset:
Structural style of Quaternary extension in the Crati Valley (Calabrian Arc); evidence in support of an east-dipping detachment fault

New geological field data, integrated with commercial seismic lines, allowed us to constrain the geometry and time-space evolution of the fault system that ruled the tectono-sedimentary evolution of the NS-striking Crati graben, in the axial portion of the northern Calabrian Arc.We highlight that this basin is controlled by a 60-km long east-dipping master fault, referred to as the Crati Graben Detachment Fault (CGDF). On the seismic sections, the CGDF appears as an east-dipping low-angle reflection reaching the surface along the eastern slope of the Catena Costiera Calabra. Its surface expression corresponds to an alignment of moderately-inclined (30° to 45°) left-stepping en-echelon faults.More to the East, a number of E- and W-dipping high-angle normal faults branch upward from the CGDF. Their reconstructed timing suggest that the westernmost faults are active since the Early Pleistocene and show a progressive eastward rejuvenation trend.The conversion to depth of a W-E oriented seismic section, crossing the entire Crati graben, highlights that the CGDF has a staircase geometry, with an average angle of 30°, and reaches a depth of 7-8 km below the east side of the basin. The evolutionary stages of the related fault system were reconstructed by restoring the section through the Move suite software (Midland Valley Exploration), in order to verify the kinematic consistency of our subsurface interpretation and estimate the amount of associate extension.Finally, the present activity and the possible seismogenic role of the CGDF is preliminarily discussed, by comparing the geometry of the extensional fault system with the available historical and seismological instrumental datasets.
Max-margin hidden conditional random fields for human action recognition

We present a new method for classification with structured latent variables. Our model is formulated using the max-margin formalism in the discriminative learning literature. We propose an efficient learning algorithm based on the cutting plane method and decomposed dual optimization. We apply our model to the problem of recognizing human actions from video sequences, where we model a human action as a global root template and a constellation of several “parts”. We show that our model outperforms another similar method that uses hidden conditional random fields, and is comparable to other state-of-the-art approaches. More importantly, our proposed work is quite general and can potentially be applied in a wide variety of vision problems that involve various complex, interdependent latent structures.
The Bioactivated Interfacial Behavior of the Fluoridated Hydroxyapatite-Coated Mg-Zn Alloy in Cell Culture Environments

A partially fluorine substituted hydroxyapatite- (FHA-) coated Mg-Zn alloy was prepared to investigate the interfacial behavior of degradable Mg-based biomaterials with degradable bioactive coatings in a cell culture environment. Peaks from the results of X-ray diffraction (XRD) were characterized and compared before and after cell culture. It was found that Ca-P, including poorly crystalline ion-substituted Ca-deficient HA (CDHA), was formed in greater amounts on the interface of coated samples compared with the uncoated ones. A thermodynamic mechanism for Ca-P formation on biodegradable Mg alloys in a cell culture environment is proposed. Combined with improved cell calcification, the-FHA coated Mg alloys have the ability to promote CDHA formation, as expected thermodynamically. It is suggested that the specific cell culture environment and the bone-like FHA coatings together facilitate the observed behavior. Moreover, cell culture environment probably increased the biomineralization to a detectable level by affecting the kinetics of apatite formation.
Novel Phenolic Inhibitors of Small/Intermediate-Conductance Ca2+-Activated K+ Channels, KCa3.1 and KCa2.3

Background KCa3.1 channels are calcium/calmodulin-regulated voltage-independent K+ channels that produce membrane hyperpolarization and shape Ca2+-signaling and thereby physiological functions in epithelia, blood vessels, and white and red blood cells. Up-regulation of KCa3.1 is evident in fibrotic and inflamed tissues and some tumors rendering the channel a potential drug target. In the present study, we searched for novel potent small molecule inhibitors of KCa3.1 by testing a series of 20 selected natural and synthetic (poly)phenols, synthetic benzoic acids, and non-steroidal anti-inflammatory drugs (NSAIDs), with known cytoprotective, anti-inflammatory, and/or cytostatic activities. Methodology/Principal Findings In electrophysiological experiments, we identified the natural phenols, caffeic acid (EC50 1.3 µM) and resveratrol (EC50 10 µM) as KCa3.1 inhibitors with moderate potency. The phenols, vanillic acid, gallic acid, and hydroxytyrosol had weak or no blocking effects. Out of the NSAIDs, flufenamic acid was moderately potent (EC50 1.6 µM), followed by mesalamine (EC50≥10 µM). The synthetic fluoro-trivanillic ester, 13b ([3,5-bis[(3-fluoro-4-hydroxy-benzoyl)oxymethyl]phenyl]methyl 3-fluoro-4-hydroxy-benzoate), was identified as a potent mixed KCa2/3 channel inhibitor with an EC50 of 19 nM for KCa3.1 and 360 pM for KCa2.3, which affected KCa1.1 and Kv channels only at micromolar concentrations. The KCa3.1/KCa2-activator SKA-31 antagonized the 13b-blockade. In proliferation assays, 13b was not cytotoxic and reduced proliferation of 3T3 fibroblasts as well as caffeic acid. In isometric vessel myography, 13b increased contractions of porcine coronary arteries to serotonin and antagonized endothelium-derived hyperpolarization-mediated vasorelaxation to pharmacological KCa3.1/KCa2.3 activation. Conclusions/Significance We identified the natural phenols, caffeic acid and resveratrol, the NSAID, flufenamic acid, and the polyphenol 13b as novel KCa3.1 inhibitors. The high potency of 13b with pan-activity on KCa3.1/KCa2 channels makes 13b a new pharmacological tool to manipulate inflammation and cancer growth through KCa3.1/KCa2 blockade and a promising template for new drug design.
A method for probing the mutational landscape of amyloid structure

Motivation: Proteins of all kinds can self-assemble into highly ordered β-sheet aggregates known as amyloid fibrils, important both biologically and clinically. However, the specific molecular structure of a fibril can vary dramatically depending on sequence and environmental conditions, and mutations can drastically alter amyloid function and pathogenicity. Experimental structure determination has proven extremely difficult with only a handful of NMR-based models proposed, suggesting a need for computational methods. Results: We present AmyloidMutants, a statistical mechanics approach for de novo prediction and analysis of wild-type and mutant amyloid structures. Based on the premise of protein mutational landscapes, AmyloidMutants energetically quantifies the effects of sequence mutation on fibril conformation and stability. Tested on non-mutant, full-length amyloid structures with known chemical shift data, AmyloidMutants offers roughly 2-fold improvement in prediction accuracy over existing tools. Moreover, AmyloidMutants is the only method to predict complete super-secondary structures, enabling accurate discrimination of topologically dissimilar amyloid conformations that correspond to the same sequence locations. Applied to mutant prediction, AmyloidMutants identifies a global conformational switch between Aβ and its highly-toxic ‘Iowa’ mutant in agreement with a recent experimental model based on partial chemical shift data. Predictions on mutant, yeast-toxic strains of HET-s suggest similar alternate folds. When applied to HET-s and a HET-s mutant with core asparagines replaced by glutamines (both highly amyloidogenic chemically similar residues abundant in many amyloids), AmyloidMutants surprisingly predicts a greatly reduced capacity of the glutamine mutant to form amyloid. We confirm this finding by conducting mutagenesis experiments. Availability: Our tool is publically available on the web at http://amyloid.csail.mit.edu/. Contact: lindquist_admin@wi.mit.edu; bab@csail.mit.edu Supplementary information: Supplementary data are available at Bioinformatics online.
Dosimetric comparison of intensity modulated radiotherapy isocentric field plans and field in field (FIF) forward plans in the treatment of breast cancer

The present study is aimed at comparing the planning and delivery efficiency between three-dimensional conformal radiotherapy (3D-CRT), field-in-field, forward planned, intensity modulated radiotherapy (FIF-FP-IMRT), and inverse planned intensity modulated radiotherapy (IP-IMRT). Treatment plans of 20 patients with left-sided breast cancer, 10 post-mastectomy treated to a prescribed dose of 45 Gy to the chest wall in 20 fractions, and 10 post-breast-conserving surgery to a prescribed dose of 50 Gy to the whole breast in 25 fractions, with 3D-CRT were selected. The FiF-FP-IMRT plans were created by combining two open fields with three to four segments in two tangential beam directions. Eight different beam directions were chosen to create IP-IMRT plans and were inversely optimized. The homogeneity of dose to planning target volume (PTV) and the dose delivered to heart and contralateral breast were compared among the techniques in all the 20 patients. All the three radiotherapy techniques achieved comparable radiation dose delivery to PTV-95% of the prescribed dose covering > 95% of the breast PTV. The mean volume of PTV receiving 105% (V105) of the prescribed dose was 1.7% (range 0-6.8%) for IP-IMRT, 1.9% for FP-IMRT, and 3.7% for 3D-CRT. The homogeneity and conformity indices (HI and CI) were similar for 3D-CRT and FP-IMRT, whereas the IP-IMRT plans had better conformity index at the cost of less homogeneity. The 3D-CRT and FiF-FP-IMRT plans achieved similar sparing of critical organs. The low-dose volumes (V5Gy) in the heart and lungs were larger in IP-IMRT than in the other techniques. The value of the mean dose to the ipsilateral lung was higher for IP-IMRT than the values for with FiF-FP-IMRT and 3D-CRT. In the current study, the relative volume of contralateral breast receiving low doses (0.01, 0.6, 1, and 2Gy) was significantly lower for the FiF-FP-IMRT and 3D-CRT plans than for the IP-IMRT plan. Compared with 3D-CRT and IP-IMRT, FiF-FP-IMRT proved to be a simple and efficient planning technique for breast irradiation. It provided dosimetric advantages, significantly reducing the size of the hot spot and minimally improving the coverage of the target volume. In addition, it was felt that FiF-FP-IMRT required less planning time and easy field placements.
Volatile-Mediated Killing of Arabidopsis thaliana by Bacteria Is Mainly Due to Hydrogen Cyanide

ABSTRACT The volatile-mediated impact of bacteria on plant growth is well documented, and contrasting effects have been reported ranging from 6-fold plant promotion to plant killing. However, very little is known about the identity of the compounds responsible for these effects or the mechanisms involved in plant growth alteration. We hypothesized that hydrogen cyanide (HCN) is a major factor accounting for the observed volatile-mediated toxicity of some strains. Using a collection of environmental and clinical strains differing in cyanogenesis, as well as a defined HCN-negative mutant, we demonstrate that bacterial HCN accounts to a significant extent for the deleterious effects observed when growing Arabidopsis thaliana in the presence of certain bacterial volatiles. The environmental strain Pseudomonas aeruginosa PUPa3 was less cyanogenic and less plant growth inhibiting than the clinical strain P. aeruginosa PAO1. Quorum-sensing deficient mutants of C. violaceum CV0, P. aeruginosa PAO1, and P. aeruginosa PUPa3 showed not only diminished HCN production but also strongly reduced volatile-mediated phytotoxicity. The double treatment of providing plants with reactive oxygen species scavenging compounds and overexpressing the alternative oxidase AOX1a led to a significant reduction of volatile-mediated toxicity. This indicates that oxidative stress is a key process in the physiological changes leading to plant death upon exposure to toxic bacterial volatiles.
Generalized extreme value statistics and sum of correlated variables

We show that generalized extreme value statistics—the statistics of the kth largest value among a large set of random variables—can be mapped onto a problem of random sums. This allows us to identify classes of non-identical and (generally) correlated random variables with a sum distributed according to one of the three (k-dependent) asymptotic distributions of extreme value statistics, namely the Gumbel, Frechet and Weibull distributions. These classes, as well as the limit distributions, are naturally extended to real values of k, thus providing a clear interpretation to the onset of Gumbel distributions with non-integer index k in the statistics of global observables. This is one of the very few known generalizations of the central limit theorem to non-independent random variables. Finally, in the context of a simple physical model, we relate the index k to the ratio of the correlation length to the system size, which remains finite in strongly correlated systems.
Linkage disequilibrium and allele-frequency distributions for 114 single-nucleotide polymorphisms in five populations.

Single-nucleotide polymorphisms (SNPs) may be extremely important for deciphering the impact of genetic variation on complex human diseases. The ultimate value of SNPs for linkage and association mapping studies depends in part on the distribution of SNP allele frequencies and intermarker linkage disequilibrium (LD) across populations. Limited information is available about these distributions on a genomewide scale, particularly for LD. Using 114 SNPs from 33 genes, we compared these distributions in five American populations (727 individuals) of African, European, Chinese, Hispanic, and Japanese descent. The allele frequencies were highly correlated across populations but differed by >20% for at least one pair of populations in 35% of SNPs. The correlation in LD was high for some pairs of populations but not for others (e.g., Chinese American or Japanese American vs. any other population). Regardless of population, average minor-allele frequencies were significantly higher for SNPs in noncoding regions (20%-25%) than for SNPs in coding regions (12%-16%). Interestingly, we found that intermarker LD may be strongest with pairs of SNPs in which both markers are nonconservative substitutions, compared to pairs of SNPs where at least one marker is a conservative substitution. These results suggest that population differences and marker location within the gene may be important factors in the selection of SNPs for use in the study of complex disease with linkage or association mapping methods.
Anti-Epidermal Growth Factor Receptor (EGFR) Antibodies Overcome Resistance of Ovarian Cancer Cells to Targeted Therapy and Natural Cytotoxicity

The poor outcome of advanced ovarian cancer under conventional therapy stimulated the exploration of new strategies to improve therapeutic efficacy. In our preclinical in vitro study we investigated a combination of targeted therapy and immunotherapy. Combination treatment with the anti-EGFR-antibody Cetuximab, related tyrosine kinase inhibitors (TKI) and cytolytic NK cells was tested against different ovarian cancer cell lines and primary tumour cells cultured from patient ascites. We found that selected ovarian cancer cells were susceptible to cetuximab and anti-EGFR-TKI-treatment, while the majority of cell lines were resistant to single or combination treatment with both substances. In addition, most ovarian cancer cells displayed low susceptibility to natural cytotoxicity of unstimulated NK cells. Notably, NK cytotoxicity against resistant ovarian cancer cells could be effectively enhanced by addition of Cetuximab mediating antibody-dependent cellular cytotoxicity (ADCC). Neither natural cytotoxicity nor ADCC of NK cells were negatively affected by the presence of TKIs. ADCC could be further increased when NK cells were pre-stimulated with monocytes and the immunostimulatory mycobacterial protein PstS-1. Our data suggest that targeted antibody therapy could be beneficial even against resistant tumour cells by augmenting supplementary cytolytic NK functions. Future studies should evaluate the combination of targeted therapy and immunotherapeutic approaches in patients with advanced ovarian cancer being resistant to standard treatment.
Robust Traffic Sign Recognition Based on Color Global and Local Oriented Edge Magnitude Patterns

Most of the existing traffic sign recognition (TSR) systems make use of the inner region of the signs or the local features such as Haar, histograms of oriented gradients (HOG), and scale-invariant feature transform for recognition, whereas these features are still limited to deal with the rotation, illumination, and scale variations situations. A good feature of a traffic sign is desired to be discriminative and robust. In this paper, a novel Color Global and Local Oriented Edge Magnitude Pattern (Color Global LOEMP) is proposed. The Color Global LOEMP is a framework that is able to effectively combine color, global spatial structure, global direction structure, and local shape information and balance the two concerns of distinctiveness and robustness. The contributions of this paper are as follows: 1) color angular patterns are proposed to provide the color distinguishing information; 2) a context frame is established to provide global spatial information, due to the fact that the context frame is established by the shape of the traffic sign, thus allowing the cells to be aligned well with the inside part of the traffic sign even when rotation and scale variations occur; and 3) a LOEMP is proposed to represent each cell. In each cell, the distribution of the orientation patterns is described by the HOG feature, and then, each direction of HOG is represented in detail by the occurrence of local binary pattern histogram in this direction. Experiments are performed to validate the effectiveness of the proposed approach with TSR systems, and the experimental results are satisfying, even for images containing traffic signs that have been rotated, damaged, altered in color, or undergone affine transformations or images that were photographed under different weather or illumination conditions.
Radiation Dose Estimates From Cardiac Multislice Computed Tomography in Daily Practice: Impact of Different Scanning Protocols on Effective Dose Estimates

Background— Multislice computed tomography angiography (CTA) is a promising technology for imaging patients with suspected coronary artery disease. Compared with 16-slice CTA, the improved spatial and temporal resolution of 64-slice CTA (0.6- versus 1.0-mm slice thickness and 330- versus 420-ms gantry rotation time) is associated with an increase in radiation dose. The objective of this retrospective investigation was to compare the estimated dose received during 16- and 64-slice CTA in daily practice and to investigate the impact of different scan protocols on dose and image quality. Methods and Results— Radiation dose was estimated for 1035 patients undergoing coronary CTA. Scanning algorithms with and without an ECG-dependent dose modulation and with a reduced tube voltage were investigated on dose estimates and image quality. In the entire patient cohort, radiation dose estimates were 6.4±1.9 and 11.0±4.1 mSv for 16- and 64-slice CTA, respectively (P<0.01). The reduction in radiation dose estimates ranged between 37% and 40% and between 53% and 64% with the use of ECG-dependent dose modulation and with the combined use of the dose modulation and a reduced tube voltage, respectively. The reduction in dose estimates was not associated with a reduction in diagnostic image quality as assessed by the signal-to-noise ratio and by the frequency of coronary segments with diagnostic image quality. Conclusions— The increase in spatial and temporal resolution with 64-slice CTA is associated with an increased radiation dose for coronary CTA. Dose-saving algorithms are very effective in reducing radiation exposure and should be used whenever possible.
ERBB3/HER2 Signaling Promotes Resistance to EGFR Blockade in Head and Neck and Colorectal Cancer Models

EGFR blocking antibodies are approved for the treatment of colorectal cancer and head and neck squamous cell carcinoma (HNSCC). Although ERBB3 signaling has been proposed to limit the effectiveness of EGFR inhibitors, the underlying molecular mechanisms are not fully understood. To gain insight into these mechanisms, we generated potent blocking antibodies against ERBB3 (REGN1400) and EGFR (REGN955). We show that EGFR and ERBB3 are coactivated in multiple HNSCC cell lines and that combined blockade of EGFR and ERBB3 inhibits growth of these cell lines more effectively than blockade of either receptor alone. Blockade of EGFR with REGN955 strongly inhibited activation of ERK in HNSCC cell lines, whereas blockade of ERBB3 with REGN1400 strongly inhibited activation of Akt; only the combination of the 2 antibodies blocked both of these essential downstream pathways. We used a HER2 blocking antibody to show that ERBB3 phosphorylation in HNSCC and colorectal cancer cells is strictly dependent on association with HER2, but not EGFR, and that neuregulin 1 activates ERBB3/HER2 signaling to reverse the effect of EGFR blockade on colorectal cancer cell growth. Finally, although REGN1400 and REGN955 as single agents slowed the growth of HNSCC and colorectal cancer xenografts, the combination of REGN1400 plus REGN955 caused significant tumor regression. Our results indicate that activation of the Akt survival pathway by ERBB3/HER2 limits the effectiveness of EGFR inhibition, suggesting that REGN1400, which is currently in a phase I clinical trial, could provide benefit when combined with EGFR blocking antibodies. Mol Cancer Ther; 13(5); 1345–55. ©2014 AACR.
Fluid pressure and flow as a cause of bone resorption

Background Unstable implants in bone become surrounded by an osteolytic zone. This is seen around loose screws, for example, but may also contribute to prosthetic loosening. Previous animal studies have shown that such zones can be induced by fluctuations in fluid pressure or flow, caused by implant instability. Method To understand the roles of pressure and flow, we describe the 3-dimensional distribution of osteolytic lesions in response to fluid pressure and flow in a previously reported rat model of aseptic loosening. 50 rats had a piston inserted in the proximal tibia, designed to produce 20 local spikes in fluid pressure of a clinically relevant magnitude (700 mmHg) twice a day. The spikes lasted for about 0.3 seconds. After 2 weeks, the pressure was measured in vivo, and the osteolytic lesions induced were studied using micro-CT scans. Results Most bone resorption occurred at pre-existing cavities within the bone in the periphery around the pressurized region, and not under the piston. This region is likely to have a higher fluid flow and less pressure than the area just beneath the piston. The velocity of fluid flow was estimated to be very high (roughly 20 mm/s). Interpretation The localization of the resorptive lesions suggests that high-velocity fluid flow is important for bone resorption induced by instability.