Miracle-dz/UniFAR-FTUs huggingface dataset:
Natural Variants of the KPC-2 Carbapenemase have Evolved Increased Catalytic Efficiency for Ceftazidime Hydrolysis at the Cost of Enzyme Stability

The spread of β-lactamases that hydrolyze penicillins, cephalosporins and carbapenems among Gram-negative bacteria has limited options for treating bacterial infections. Initially, Klebsiella pneumoniae carbapenemase-2 (KPC-2) emerged as a widespread carbapenem hydrolyzing β-lactamase that also hydrolyzes penicillins and cephalosporins but not cephamycins and ceftazidime. In recent years, single and double amino acid substitution variants of KPC-2 have emerged among clinical isolates that show increased resistance to ceftazidime. Because it confers multi-drug resistance, KPC β-lactamase is a threat to public health. In this study, the evolution of KPC-2 function was determined in nine clinically isolated variants by examining the effects of the substitutions on enzyme kinetic parameters, protein stability and antibiotic resistance profile. The results indicate that the amino acid substitutions associated with KPC-2 natural variants lead to increased catalytic efficiency for ceftazidime hydrolysis and a consequent increase in ceftazidime resistance. Single substitutions lead to modest increases in catalytic activity while the double mutants exhibit significantly increased ceftazidime hydrolysis and resistance levels. The P104R, V240G and H274Y substitutions in single and double mutant combinations lead to the largest increases in ceftazidime hydrolysis and resistance. Molecular modeling suggests that the P104R and H274Y mutations could facilitate ceftazidime hydrolysis through increased hydrogen bonding interactions with the substrate while the V240G substitution may enhance backbone flexibility so that larger substrates might be accommodated in the active site. Additionally, we observed a strong correlation between gain of catalytic function for ceftazidime hydrolysis and loss of enzyme stability, which is in agreement with the ‘stability-function tradeoff’ phenomenon. The high Tm of KPC-2 (66.5°C) provides an evolutionary advantage as compared to other class A enzymes such as TEM (51.5°C) and CTX-M (51°C) in that it can acquire multiple destabilizing substitutions without losing the ability to fold into a functional enzyme.
Opposite Movement of the External Gate of a Glutamate Transporter Homolog upon Binding Cotransported Sodium Compared with Substrate

Recently, a new model for glutamate uptake by glutamate transporters was proposed based on crystal structures of the bacterial glutamate transporter homolog GltPh. It was proposed that hairpin two (HP2) functions as the extracellular gate and that Na+ and glutamate binding closes HP2, thereby allowing for the translocation of the glutamate binding pocket across the membrane. However, the conformation of HP2 in the apo state and the Na+ bound state is unknown. We here use double site-directed spin-labeling electron paramagnetic resonance spectroscopy on the bacterial transporter GltPh from Pyrococcus horikoshi to examine conformational changes in HP2. Surprisingly, the cotransported substrates Na+ and aspartate induce opposite movements of HP2. We find that in the apo state, HP2 is in a similar conformation as in the aspartate-bound closed state. Na+ binding to the apo state opens HP2, whereas the subsequent binding of aspartate closes HP2. Our findings show that Na+ binding opens and stabilizes the extracellular gate, thereby allowing for amino acid substrate binding. In contrast, in the absence of Na+ and aspartate, HP2 closes, suggesting a potential mechanism for the translocation of the empty binding pocket necessary to complete the transport cycle. The finding that physiological Na+ concentrations stabilize the open HP2 state would ensure that the outward-facing conformation of the transporter is maintained in physiological solutions and that glutamate transporters are ready to quickly bind glutamate released from glutamatergic synapses.
What Triggers a Diagnosis of HIV Infection in the Tokyo Metropolitan Area? Implications for Preventing the Spread of HIV Infection in Japan

Background Japan has not succeeded in reducing the annual number of new HIV-infected patients, although the prevalence of HIV infection is low (0.02%). Methods A single-center observational study was conducted at the largest HIV clinic in Tokyo, which treats 15% of the total patients in Japan, to determine the reasons for having diagnostic tests in newly infected individuals. HIV-infected patients who visited our clinic for the first time between 2011 and 2014 were analyzed. Results The 598 study patients comprised one-third of the total reported number of new patients in Tokyo during the study period. 76% were Japanese MSM. The reasons for being tested which led to the diagnosis was voluntary testing in 32%, existing diseases in 53% (AIDS-defining diseases in 22%, sexually transmitted infections (STI) in 8%, diseases other than AIDS or STIs in 23%) and routine pre-surgery or on admission screening in 15%. 52% and 74% of the study patients and patients presented with AIDS, respectively, had never been tested. The median CD4 count in patients with history of previous testing (315/μL) was significantly higher than that of patients who had never been tested (203/μL, p<0.001). Conclusions Only 32% of the newly HIV diagnosed patients were diagnosed because of voluntary testing, and 53% were diagnosed due to presence of other diseases. These results remain unchanged from our previous report 10 years earlier (2000–2004) on newly diagnosed patients at the same clinic. HIV testing has not been widely used by newly diagnosed patients in the Tokyo metropolitan area.
What Software Repositories Should Be Mined for Defect Predictors?

The information about which modules in a software system's future version are potentially defective is a valuable aid for quality managers and testers. Defect prediction promises to indicate these defect-prone modules. Constructing effective defect prediction models in an industrial setting involves the decision from what data source the defect predictors should be derived. In this paper we compare defect prediction results based on three different data sources of a large industrial software system to answer the question what repositories to mine. In addition, we investigate whether a combination of different data sources improves the prediction results. The findings indicate that predictors derived from static code and design analysis provide slightly yet still significant better results than predictors derived from version control, while a combination of all data sources showed no further improvement.
Tumor Budding, Micropapillary Pattern, and Polyploidy Giant Cancer Cells in Colorectal Cancer: Current Status and Future Prospects

We previously reported that polyploid giant cancer cells (PGCGs) induced by CoCl2 could form through endoreduplication or cell fusion. A single PGCC formed tumors in immunodeficient mice. PGCCs are also the key contributors to the cellular atypia and associate with the malignant grade of tumors. PGCCs have the properties of cancer stem cells and produce daughter cells via asymmetric cell division. Compared with diploid cancer cells, these daughter cells express less epithelial markers and acquire mesenchymal phenotype with importance in cancer development and progression. Tumor budding is generally recognized to correlate with a high recurrence rate, lymph node metastasis, chemoresistance, and poor prognosis of colorectal cancers (CRCs) and is a good indicator to predict the metastasis and aggressiveness in CRCs. Micropapillary pattern is a special morphologic pattern and also associates with tumor metastasis and poor prognosis. There are similar morphologic features and molecular phenotypes among tumor budding, micropapillary carcinoma pattern, and PGCCs with their budding daughter cells and all of them show strong ability of tumor invasion and migration. In this review, we discuss the cancer stem cell properties of PGCCs, the molecular mechanisms of their regulation, and the relationships with tumor budding and micropapillary pattern in CRCs.
A Preclinical Assessment of Neural Stem Cells as Delivery Vehicles for Anti-Amyloid Therapeutics

Transplantation of neural stems cells (NSCs) could be a useful means to deliver biologic therapeutics for late-stage Alzheimer's disease (AD). In this study, we conducted a small preclinical investigation of whether NSCs could be modified to express metalloproteinase 9 (MMP9), a secreted protease reported to degrade aggregated Aβ peptides that are the major constituents of the senile plaques. Our findings illuminated three issues with using NSCs as delivery vehicles for this particular application. First, transplanted NSCs generally failed to migrate to amyloid plaques, instead tending to colonize white matter tracts. Second, the final destination of these cells was highly influenced by how they were delivered. We found that our injection methods led to cells largely distributing to white matter tracts, which are anisotropic conduits for fluids that facilitate rapid distribution within the CNS. Third, with regard to MMP9 as a therapeutic to remove senile plaques, we observed high concentrations of endogenous metalloproteinases around amyloid plaques in the mouse models used for these preclinical tests with no evidence that the NSC-delivered enzymes elevated these activities or had any impact. Interestingly, MMP9-expressing NSCs formed substantially larger grafts. Overall, we observed long-term survival of NSCs in the brains of mice with high amyloid burden. Therefore, we conclude that such cells may have potential in therapeutic applications in AD but improved targeting of these cells to disease-specific lesions may be required to enhance efficacy.
Low level visual feature extraction by learning of multiple tasks for Convolutional Neural Networks

Visual features trained from large scale image data by the deep convolutional neural network can be used for the other visual tasks. This paper investigates the effects of the learning of multiple tasks for such transfer learning from the source domains to the target domain. Two methods of the learning of multiple tasks are considered. Also we investigate which hidden layers should be re-trained for the target task in the fine-tuning process by selecting a subset of the hidden layers and updating only the parameters of the selected subset. Through a detail experiments, we confirmed the effectiveness of the learning of multiple tasks for pre-training. Also we showed that the first layer is not always required to be trained for the target task and the fully-connected layer, the classifier layer, and the last hidden layer should be retrained for the target task in the fine-tuning. These results suggests that the first and the second layers in the deep convolutional neural network trained by the learning of multiple tasks can extract general low level visual features.
A Bayesian Hierarchical Model for Comparing Average F1 Scores

In multi-class text classification, the performance (effectiveness) of a classifier is usually measured by micro-averaged and macro-averaged F1 scores. However, the scores themselves do not tell us how reliable they are in terms of forecasting the classifier's future performance on unseen data. In this paper, we propose a novel approach to explicitly modelling the uncertainty of average F1 scores through Bayesian reasoning, and demonstrate that it can provide much more comprehensive performance comparison between text classifiers than the traditional frequentist null hypothesis significance testing (NHST).
First detection of a minor merger a z~0.6

Numerical simulations predict that minor mergers are an important channel for the mass assembly of galaxies. However, minor mergers are relatively difficult to detect using imaging, especially at high redshift. While such events are much less violent than major mergers, they can nevertheless leave several features on the kinematical structures of remnant galaxies which could be detected using 3D spectroscopy. We present the first direct detection of a minor merger in a z~0.6 galaxy. Such events could indeed be good candidates to explain the kinematics of perturbed rotating disks observed with GIRAFFE at z~0.6. We present photometric and kinematical evidence of such an event in a combined analysis of three-band HST/ACS imaging and VLT/GIRAFFE 2D-kinematics. Using these data, we are able to demonstrate that a minor merger of a relatively small satellite (mass ratio ~1:18) is occurring in this galaxy. We also derive a total SFR ~21Mo/yr. Minor mergers could be one of the physical processes explaining the kinematics of perturbed rotating disks, which represent ~25% of emission line intermediate mass galaxies at z~0.6. 3D spectroscopy appears to be a very good tool to identify minor mergers in distant (and local) galaxies.
Performance-enhancing Effect of Eased Negotiations through Relational Governance

The aim of this study is to examine the impact of transaction cost variables (environmental uncertainty and negotiation costs) and prior cooperation as a proxy for interorganizational trust on relationship performance. This study proposes that relational governance (through prior cooperation) provides negotiation efficiency which in turn enhances relationship performance by improving the access to information and promoting situational flexibility in harmony of mutual interests and hence facilitating sequential coordinated adaptations. In this connection, prior cooperation is considered as a moderator in the relationship between negotiation costs and performance. The empirical results of this study confirm the moderating role of relational governance in improving performance. To the best of our knowledge, this study provides the first empirical evidence for the performanceenhancing effect of eased negotiations through relational governance. Therefore, we believe that this study that offers an understanding of performance enhancement based on efficiencies gained from eased negotiations contributes to the literature.
Advances in Portfolio Construction and Implementation

Modern Portfolio Theory explores how risk averse investors construct portfolios in order to optimize market risk against expected returns. The theory quantifies the benefits of diversification. Modern Portfolio Theory provides a broad context for understanding the interactions of systematic risk and reward. It has profoundly shaped how institutional portfolios are managed, and has motivated the use of passive investment management techniques, and the mathematics of MPT is used extensively in financial risk management. Advances in Portfolio Construction and Implementation offers practical guidance in addition to the theory, and is therefore ideal for Risk Mangers, Actuaries, Investment Managers, and Consultants worldwide. Issues are covered from a global perspective and all the recent developments of financial risk management are presented. Although not designed as an academic text, it should be useful to graduate students in finance. *Provides practical guidance on financial risk management *Covers the latest developments in investment portfolio construction *Full coverage of the latest cutting edge research on measuring portfolio risk, alternatives to mean variance analysis, expected returns forecasting, the construction of global portfolios and hedge portfolios (funds)
Automatic Cost Estimation for Tree Edit Distance Using Particle Swarm Optimization

Recently, there is a growing interest in working with tree-structured data in different applications and domains such as computational biology and natural language processing. Moreover, many applications in computational linguistics require the computation of similarities over pair of syntactic or semantic trees. In this context, Tree Edit Distance (TED) has been widely used for many years. However, one of the main constraints of this method is to tune the cost of edit operations, which makes it difficult or sometimes very challenging in dealing with complex problems. In this paper, we propose an original method to estimate and optimize the operation costs in TED, applying the Particle Swarm Optimization algorithm. Our experiments on Recognizing Textual Entailment show the success of this method in automatic estimation, rather than manual assignment of edit costs.
Mellin transforms for multiple Jacobi-Piñeiro polynomials

This work treats the Mellin transform of multiple Jacobi-Piñeiro polynomials. This allows us to put a number of irrationality and Q-linear independence proofs into the framework of Hermite-Padé approximation. A similar approach is presented for the q-analogue: the q-Mellin transform of multiple little q-Jacobi polynomials and its applications in irrationality proofs.
Classical chaotic trajectories in quantum field theory

Trajectories in the space of the unitarily inequivalent representations of the canonical commutation relations are shown to be classical trajectories. Under convenient conditions, they may exhibit properties typical of chaotic behavior in classical nonlinear dynamics. Quantum noise in fluctuating random force in the system–environment coupling and system–environment entanglement is also discussed.
The Effect of Venture Capital Involvement on Capital Structure Determinants *

This paper analyzes the change in the capital structure behavior in a sample of Spanish venture capital (VC) backed firms after the first capital infusion. We find that VC investors contribute to unlisted growing firms in the attraction of other long term sources of funds to continue their growth process. Our results show significant changes in determinants such as tangibility, size and profitability. Regarding tangibility and size, the entrance of an external investor seems to have a certification effect that eases the need to have either tangible assets or a large size to obtain additional debt financing. As regards profitability, the investments carried out after the initial VC investment do affect short term profitability (i.e. larger depreciation), but this situation is not linked to a restrained access to external debt. JEL classification: G32, G24.
Integrin-cytoskeletal interactions in migrating fibroblasts are dynamic, asymmetric, and regulated

We have used laser optical trapping and nanometer-level motion analysis to investigate the cytoskeletal associations and surface dynamics of beta 1 integrin, a cell-substrate adhesion molecule, on the dorsal surfaces of migrating fibroblast cells. A single-beam optical gradient trap (laser tweezers) was used to restrain polystyrene beads conjugated with anti-beta 1 integrin mAbs and place them at desired locations on the cell exterior. This technique was used to demonstrate a spatial difference in integrin-cytoskeleton interactions in migrating cells. We found a distinct increase in the stable attachment of beads, and subsequent rearward flow, on the lamellipodia of locomoting cells compared with the retracting portions. Complementary to the enhanced linkage of integrin at the cell lamellipodium, the membrane was more deformable at the rear versus the front of moving cells while nonmotile cells did not exhibit this asymmetry in membrane architecture. Video microscopy and nanometer-precision tracking routines were used to study the surface dynamics of integrin on the lamellipodia of migrating cells by monitoring the displacements of colloidal gold particles coated with anti-beta 1 integrin mAbs. Small gold aggregates were rapidly transported preferentially to the leading edge of the lamellipod where they resumed diffusion restricted along the edge. This fast transport was characterized by brief periods of directed movement ("jumps") having an instantaneous velocity of 37 +/- 15 microns/min (SD), separated by periods of diffusion. In contrast, larger aggregates of gold particles and the large latex beads underwent slow, steady rearward movement (0.85 +/- 0.44 micron/min) (SD) at a rate similar to that reported for other capping events and for migration of these cells. Cell lines containing mutated beta 1 integrins were used to show that the cytoplasmic domain is essential for an asymmetry in attachment of integrin to the underlying cytoskeletal network and is also necessary for rapid, intermittent transport. However, enhanced membrane deformability at the cell rear does not require integrin-cytoskeletal interactions. We also demonstrated that posttranslational modifications of integrin could potentially play a role in these phenomena. These results suggest a scheme for the role of dynamic integrin-mediated adhesive interactions in cell migration. Integrins are transported preferentially to the cell front where they form nascent adhesions. These adhesive structures grow in size and associate with the cytoskeleton that exerts a rearward force on them. Dorsal aggregates more rearward while those on the ventral side remain fixed to the substrate allowing the cell body to move forward. Detachment of the cell rear occurs by at least two modes: (a) weakened integrin- cytoskeleton interactions, potentially mediated by local modifications of linkage proteins, which lead to weakened cell-substratum interactions and (b) ripping of integrins and the highly deformable membrane from the cell body.
The Beta-Hyperbolic Secant Distribution

The shape of a probability distribution is often summarized by the distribution’s skewness and kurtosis. Starting from a symmetric “parent” density f on the real line, we can modify its shape (i.e. introduce skewness and in-/decrease kurtosis) if f is appropriately weighted. In particular, every density w on the interval (0, 1) is a specific weighting function. Within this work, we follow up a proposal of Jones (2004) and choose the Beta distribution as underlying weighting function w. “Parent” distributions like the Studentt, the logistic and the normal distribution have already been investigated in the literature. Based on the assumption that f is the density of a hyperbolic secant distribution, we introduce the Beta-hyperbolic secant (BHS) distribution. In contrast to the Beta-normal distribution and to the Beta-Student-t distribution, BHS densities are always unimodal and all moments exist. In contrast to the Beta-logistic distribution, the BHS distribution is more flexible regarding the range of skewness and leptokurtosis combinations. Moreover, we propose a generalization which nests both the Beta-logistic and the BHS distribution. Finally, the goodness-of-fit between all above-mentioned distributions is compared for glass fibre data and aluminium returns. Zusammenfassung: Die Gestalt einer Verteilung wird häufig zusammengefasst durch Schiefe und Kurtosis beschrieben. Wir starten mit einer symmetrischen “Eltern” Dichte f auf der reellen Achse und modifizieren ihre Gestalt (d.h. wir führen Schiefe ein und vergrößern/verkleinern die Kurtosis) indem f passend gewichtet wird. Insbesondere ist jede Dichte w auf dem reellen Intervall (0, 1) eine bestimmte Gewichtsfunktion. In dieser Arbeit folgen wir einem Vorschlag von Jones (2004) und wählen die Betaverteilung als zugrunde liegende Gewichtsfunktion w. “Eltern” Verteilungen wie die Student-t, die logistische und die Normalverteilung sind bereits in der Literatur untersucht worden. Wir nehmen an, dass f die Dichte einer Hyperbolische Schrankenverteilung ist, und führen so die Beta-Hyperbolische Schranken (BHS) Verteilung ein. Im Gegensatz zur Betanormal Verteilung und zur Beta-Student-t Verteilung sind BHS Dichten immer unimodal und alle Momente existieren. Im Gegensatz zur Beta-logistischen Verteilung ist die BHS Verteilung flexibler betreffs dem Bereich von Schiefe und Leptokurtosis Kombinationen. Zudem schlagen wir eine Verallgemeinerung vor, die sowohl die Beta-logistische als auch die BHS Verteilung enthält. Schließlich wird die Anpassungsgüte aller erwähnten Verteilungen für Glasfaser-Daten und Aluminiumpreise verglichen.