Miracle-dz/UniFAR-FTUs huggingface dataset:
“Re-educating” tumor-associated macrophages by targeting NF-κB

The nuclear factor κB (NF-κB) signaling pathway is important in cancer-related inflammation and malignant progression. Here, we describe a new role for NF-κB in cancer in maintaining the immunosuppressive phenotype of tumor-associated macrophages (TAMs). We show that macrophages are polarized via interleukin (IL)-1R and MyD88 to an immunosuppressive “alternative” phenotype that requires IκB kinase β–mediated NF-κB activation. When NF-κB signaling is inhibited specifically in TAMs, they become cytotoxic to tumor cells and switch to a “classically” activated phenotype; IL-12high, major histocompatibility complex IIhigh, but IL-10low and arginase-1low. Targeting NF-κB signaling in TAMs also promotes regression of advanced tumors in vivo by induction of macrophage tumoricidal activity and activation of antitumor activity through IL-12–dependent NK cell recruitment. We provide a rationale for manipulating the phenotype of the abundant macrophage population already located within the tumor microenvironment; the potential to “re-educate” the tumor-promoting macrophage population may prove an effective and novel therapeutic approach for cancer that complements existing therapies.
State of the science: violence prevention efforts in developing and developed countries

Violence is an important global public health problem that claims the lives of over 1.6 million people each year and results in numerous other health and social consequences. It is also a preventable health problem. This paper provides an overview of the current status of prevention efforts in developing and developed countries, describes what is known about the effectiveness of different approaches and highlights some of the important challenges in building the evidence-base for violence prevention programmes. Research conducted to date shows an imbalance in the emphasis of prevention programmes across the different types of violence. This imbalance is reflected in the timing of response, the nature and level of influence of interventions and programmes and the outcomes studied. Promising and effective approaches have been identified, but many more still require rigorous testing, particularly in developing countries. The current state of the science in violence prevention reveals both progress and a number of remaining challenges.
Combining Optimal Control Theory and Molecular Dynamics for Protein Folding

A new method to develop low-energy folding routes for proteins is presented. The novel aspect of the proposed approach is the synergistic use of optimal control theory with Molecular Dynamics (MD). In the first step of the method, optimal control theory is employed to compute the force field and the optimal folding trajectory for the atoms of a Coarse-Grained (CG) protein model. The solution of this CG optimization provides an harmonic approximation of the true potential energy surface around the native state. In the next step CG optimization guides the MD simulation by specifying the optimal target positions for the atoms. In turn, MD simulation provides an all-atom conformation whose positions match closely the reference target positions determined by CG optimization. This is accomplished by Targeted Molecular Dynamics (TMD) which uses a bias potential or harmonic restraint in addition to the usual MD potential. Folding is a dynamical process and as such residues make different contacts during the course of folding. Therefore CG optimization has to be reinitialized and repeated over time to accomodate these important changes. At each sampled folding time, the active contacts among the residues are recalculated based on the all-atom conformation obtained from MD. Using the new set of contacts, the CG potential is updated and the CG optimal trajectory for the atoms is recomputed. This is followed by MD. Implementation of this repetitive CG optimization - MD simulation cycle generates the folding trajectory. Simulations on a model protein Villin demonstrate the utility of the method. Since the method is founded on the general tools of optimal control theory and MD without any restrictions, it is widely applicable to other systems. It can be easily implemented with available MD software packages.
Updating Sets of Probabilities

There are several well-known justifications for conditioning as the appropriate method for updating a single probability measure, given an observation. However, there is a significant body of work arguing for sets of probability measures, rather than single measures, as a more realistic model of uncertainty. Conditioning still makes sense in this context--we can simply condition each measure in the set individually, then combine the results--and, indeed, it seems to be the prel ferred updating procedure in the literature. But how justified is conditioning in this richer setting? Here we show, by considering an axiomatic account of conditioning given by van Fraassen, that the single-measure and sets-of-measures cases are very different. We show that van Fraassen's axiomatization for the former case is nowhere near sufficient for updating sets of measures. We give a considerably longer (and not as compelling) list of axioms that together force conditioning in this setting, and describe other update methods that are allowed once any of these axioms is dropped.
Mesenchymal Stem Cells and Endothelial Progenitor Cells Decrease Renal Injury in Experimental Swine Renal Artery Stenosis Through Different Mechanisms

Endothelial progenitor cells (EPC) and mesenchymal stem cells (MSC) augment tissue repair but possess slightly different properties. How the cellular phenotype affects the efficacy of this approach in renovascular disease is incompletely understood. This study tested the hypothesis that EPC and MSC protect the poststenotic kidney by blunting different disease pathways. Peripheral blood EPC and adipose‐derived MSC were expanded and characterized by cell surface markers (e.g., CD34/kinase insert domain receptor, or CD44/CD90). Single‐kidney hemodynamics and function were assessed in pigs after 10 weeks of renal artery stenosis (RAS) treated 4 weeks earlier with an intrarenal infusion of vehicle (n = 7), EPC (RAS+EPC) or MSC (RAS+MSC) (both 10 × 106, n = 6), and normal controls (n = 7). Kidney disease mechanisms were evaluated ex vivo. The ability of EPC and MSC to attenuate endoplasmic reticulum (ER) stress was also studied in isolated ER and in tubular cells cocultured with EPC and MSC. Glomerular filtration rate in RAS was lower than controls, increased in RAS+EPC, and further improved in RAS+MSC, although both improved renal blood flow similarly. EPC prominently enhanced renal growth factor expression and decreased oxidative stress, while MSC more significantly attenuated renal inflammation, ER stress, and apoptosis. Furthermore, MSC induced a greater decrease in caspase‐3 and CHOP expression in cultured tubular cells through mechanisms involving cell contact. EPC and MSC achieve a comparable decrease of kidney injury in RAS by different mechanisms, although MSC elicited slightly superior improvement of renal function. These results support development of cell‐based approaches for management of renovascular disease and suggest cell selection based on the underlying pathophysiology of kidney injury. STEM Cells2013;31:117–125
A Novel Motif in Fungal Class 1 Histone Deacetylases Is Essential for Growth and Development of Aspergillus

A C-terminal motif of an A. nidulans class 1 histone deacetylase (HDAC) is required for catalytic activity and viability of the fungus. Moreover, this motif seems to play a decisive role for growth and development of other fungal species. Thus, this enzyme/motif may represent a promising target for HDAC-inhibitors acting as antifungal agents.
Ubiquitous Log Odds: A Common Representation of Probability and Frequency Distortion in Perception, Action, and Cognition

In decision from experience, the source of probability information affects how probability is distorted in the decision task. Understanding how and why probability is distorted is a key issue in understanding the peculiar character of experience-based decision. We consider how probability information is used not just in decision-making but also in a wide variety of cognitive, perceptual, and motor tasks. Very similar patterns of distortion of probability/frequency information have been found in visual frequency estimation, frequency estimation based on memory, signal detection theory, and in the use of probability information in decision-making under risk and uncertainty. We show that distortion of probability in all cases is well captured as linear transformations of the log odds of frequency and/or probability, a model with a slope parameter, and an intercept parameter. We then consider how task and experience influence these two parameters and the resulting distortion of probability. We review how the probability distortions change in systematic ways with task and report three experiments on frequency distortion where the distortions change systematically in the same task. We found that the slope of frequency distortions decreases with the sample size, which is echoed by findings in decision from experience. We review previous models of the representation of uncertainty and find that none can account for the empirical findings.
Distance-dependent association of affect with pacing strategy in cycling time trials.

UNLABELLED The psychological construct of affect is proposed to significantly contribute to pacing decisions during exercise. Borg's RPE scale, another important regulator of work rate, is criticized as an inadequate measure of the multiple perceptual responses experienced. This study aimed to examine power output distribution and associated changes in affect, self-efficacy, perceptual cues, HR, and respiratory gases during both 16.1- and 40-km self-paced cycling time trials (TT). Secondly, the differentiation between physical perceptions of exertion and sense of effort in self-paced exercise was investigated. METHOD Fifteen trained male cyclists completed 16.1- and 40-km TT using a CompuTrainer cycle ergometer. Time, power output distribution, affect, self-efficacy, physical RPE (P-RPE), task effort and awareness (TEA), HR, and respiratory gases were measured throughout each TT. Linear mixed models explored associations of these variables with power output distribution and the relationship between P-RPE and TEA. RESULTS Similar pacing strategies were adopted in the 16.1- and 40-km TT (P = 0.31), and the main effects were found for affect (P = 0.001) and RER (P < 0.001). Interactions between affect (P = 0.037) and RER (P = 0.004), with condition, indicated closer associations with power output distribution in 16.1 km than that in 40 km TT. P-RPE was not significantly different from TEA (P = 0.053). CONCLUSION A significant association between affect and power output distribution suggests that affective responses are task dependent even in self-paced exercise, and a greater association is demonstrated in higher intensity, 16.1 km TT. Furthermore, physical perceptions of exertion are not clearly differentiated from the sense of effort in self-paced exercise.
A Revised Subduction Inception Model to Explain the Late Cretaceous, Double‐Vergent Orogen in the Precollisional Western Tethys: Evidence From the Northern Apennines

The Meso‐Cenozoic alpine belts of the Mediterranean area are characterized by complex architectures, result of a complex subduction and collision evolution that preserve also a legacy of the rifting‐related configuration of the continental margins. The Northern Apennines is a segment of these belts originated during closure of the Ligure‐Piemontese ocean and collision between the Europe and Adria plates. The different configuration of the Adria and Europe margins, inherited from asymmetric rifting, is recorded in the Ligurian Units that preserve incorporation into the subduction factory of fragments of the oceanic domain (Internal Ligurian Units) and portions of the Ocean‐Continent Transition Zone (OCTZ) toward Adria (External Ligurian Units). We provide here unpublished data on the stratigraphy and sedimentology of these units, together with a review of what is already established in literature. Both data sets combined testify that at 80 Ma, an accretionary prism was growing between the deposition basins of the two groups of units and fed both basins with clasts from the ocean realm, the continental crust, and the subcontinental mantle. We propose that closure of the Ligure‐Piemontese ocean occurred through subduction that nucleated at the transition from the oceanic plate and the thinned Adria margin and developed a double‐vergent prism by accreting oceanic material and continental extensional allochthons from the OCTZ. We believe the revised site of subduction initiation, and the precollisional architecture, inherited from the rifting and spreading phases, allows reconciling most of the discrepancies between the various interpretations proposed in literature for the precollisional evolution of the Apennines.
What Syndrome Is This?

A 1-week-old African infant male was admitted with an unusual constellation of findings. He was born after an uncomplicated, full-term first pregnancy of a 22-year-old mother. His parents were healthy and unrelated. The mother denied taking any medication during pregnancy. The infant was alert and did not appear ill. On examination several abnormalities were noted, including generalized hypertrichosis, most pronounced over the mid-back (Fig. 1), a dysmorphic facies with bilateral ectropion, hypertelorism, macrostomia, abnormally shaped ears, bulbous nose, and sparse eyebrows and eyelashes (Fig. 2). He also had hypoplasia of the nipples, transposition of the scrotum (shawl scrotum) (Fig. 3), club feet, a short neck, and laxity of the skin. A skin biopsy specimen from the right thigh showed an atrophic, slightly orthohyperkeratotic epidermis, and a thin reticular layer of dermis. Staining for elastic fibers showed a diminution in number and fragmentation (Fig. 4). The karyotype was normal. Radiographic examination of the axial skeleton, skull sonar, and abdominal echography were normal. Laboratory tests including full blood count, serum urea and electrolytes, serum proteins, liver enzymes, and glucose had normal results.
Photoscan localization of GW-39 tumors in hamsters using radiolabeled anticarcinoembryonic antigen immunoglobulin G.

Summary Photoscans and organ radioactivity were assessed in hamsters bearing cheek pouch grafts of a carcinoembryonic antigen (CEA)-producing human colonic carcinoma, GW-39; a human sarcoma, H.S. 1; and a hamster amelanotic melanoma, A.Mel. 3. The animals were given injections of 10 to 50 μCi 125I-labeled heterospecific anti-CEA immunoglobulin G (IgG) or normal IgG. The photoscans showed an increased uptake of radioactivity over the tumors and frequently over the areas of the thorax and urinary bladder, regardless of the tumor or the radiolabeled IgG preparation used. Even normal hamsters receiving either radiolabeled preparation showed an increased accretion of radioactivity over the thoracic region. A specific tumor localization, however, was demonstrated in animals bearing small ( The radioactivity recovered from GW-39 tumors borne in hamsters given injections of radiolabeled anti-CEA IgG revealed an increase of 7.5 to 20 times that recovered from other tissues. A slightly increased uptake of either the specific or nonspecific radiolabeled preparation was seen in the other, non-CEA-producing tumors studied, which was sufficiently increased over background radiation to permit visualization of the tumors by photoscanning, especially when the neoplasms were large and vascular. Evidently radiolabeled nonantibody components of heterospecific IgG can be localized in certain tumors and normal tissues by photoscanning. Nevertheless, tumor localization due to an antigen-antibody reaction, as we have found in CEA-producing GW-39 tumors treated with an anti-CEA antibody preparation, permits photoscan visualization of tumors too small to be demonstrated by radiolabeled normal IgG. It thus appears that CEA is a suitable tumor target for radioantibody by photoscanning.
Understanding Consumer Behavior with the Use of the Technology Acceptance Model in Online Booking

This study aimed to examine consumer buying intention using the Technology Acceptance Model (TAM). This study seeked to determine the direct effect of perceived usefulness, perceived ease of use, and perceived trust on buying intention through online booking applications. This type of research was explanatory, which explained the causal relationship between the variables and used a quantitative approach. The population used in this study was all people who had installed online booking applications. The sampling method of 450 respondents in this study was nonprobability sampling with a purposive sampling technique, whereby the questionnaire was distributed in the form of a survey through social media. Hypothesis testing was carried out using the t-test. Data analysis used multiple linear regression analysis, which was processed with SPSS software. From the results of testing the three hypotheses that had been carried out, it was concluded that the variables of perceived usefulness, perceived ease of use, and perceived trust had a significant and positive effect on the variable of buying intention through online booking applications. Keywords: consumer behavior, Technology Acceptance Model, online booking
A Trust Evaluation Algorithm for Wireless Sensor Networks Based on Node Behaviors and D-S Evidence Theory

For wireless sensor networks (WSNs), many factors, such as mutual interference of wireless links, battlefield applications and nodes exposed to the environment without good physical protection, result in the sensor nodes being more vulnerable to be attacked and compromised. In order to address this network security problem, a novel trust evaluation algorithm defined as NBBTE (Node Behavioral Strategies Banding Belief Theory of the Trust Evaluation Algorithm) is proposed, which integrates the approach of nodes behavioral strategies and modified evidence theory. According to the behaviors of sensor nodes, a variety of trust factors and coefficients related to the network application are established to obtain direct and indirect trust values through calculating weighted average of trust factors. Meanwhile, the fuzzy set method is applied to form the basic input vector of evidence. On this basis, the evidence difference is calculated between the indirect and direct trust values, which link the revised D-S evidence combination rule to finally synthesize integrated trust value of nodes. The simulation results show that NBBTE can effectively identify malicious nodes and reflects the characteristic of trust value that ‘hard to acquire and easy to lose’. Furthermore, it is obvious that the proposed scheme has an outstanding advantage in terms of illustrating the real contribution of different nodes to trust evaluation.
A Regulatory Role for Sphingolipids in Neuronal Growth

Sphingolipids, particularly gangliosides, are enriched in neuronal membranes where they have been implicated as mediators of various regulatory events. We recently provided evidence that sphingolipid synthesis is necessary to maintain neuronal growth by demonstrating that in hippocampal neurons, inhibition of ceramide synthesis by Fumonisin B1 (FB1) disrupted axonal outgrowth (Harel, R. and Futerman, A. H. (1993) J. Biol. Chem. 268, 14476-14481). We now analyze further the relationship between neuronal growth and sphingolipid metabolism by examining the effect of an inhibitor of glucosylceramide synthesis, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) and by examining the effects of both FB1 and PDMP at various stages of neuronal development. No effects of FB1 or PDMP were observed during the first 2 days in culture, but by day 3 axonal morphology was significantly altered, irrespective of the time of addition of the inhibitors to the cultures. Cells incubated with FB1 or PDMP had a shorter axon plexus and less axonal branches. FB1 appeared to cause a retraction of axonal branches between days 2 and 3, although long term incubation had no apparent effect on neuronal morphology or on the segregation of axonal or dendritic proteins. In contrast, incubation of neurons with conduritol B-epoxide, an inhibitor of glucosylceramide degradation, caused an increase in the number of axonal branches and a corresponding increase in the length of the axon plexus. A direct correlation was observed between the number of axonal branch points per cell and the extent of inhibition of either sphingolipid synthesis or degradation. These results suggest that sphingolipids play an important role in the formation or stabilization of axonal branches.
Differential gradients of interaction affinities drive efficient targeting and recycling in the GET pathway

Significance Ensuring the accuracy of protein interaction cascades is a challenge in many cellular processes. This challenge is faced by the guided entry of tail-anchored (TA) protein (GET) pathway, in which the targeting factor Get3 must sequentially interact with three effector proteins to deliver an essential class of TA proteins to the membrane. Using fluorescence probes that quantitatively interrogate individual Get3–effector interactions, we show here that Get3 adopts discrete conformational states in response to substrate and nucleotide binding; these conformational states allow Get3 to generate differential gradients of interaction energies with distinct effectors, thus driving its cyclic and ordered interaction cascade. These results also explain why multiple effector proteins are needed for TA targeting and uncover a previously unidentified mechanism for recycling Get3 from the membrane. Efficient and accurate localization of membrane proteins requires a complex cascade of interactions between protein machineries. This requirement is exemplified in the guided entry of tail-anchored (TA) protein (GET) pathway, where the central targeting factor Get3 must sequentially interact with three distinct binding partners to ensure the delivery of TA proteins to the endoplasmic reticulum (ER) membrane. To understand the molecular principles that provide the vectorial driving force of these interactions, we developed quantitative fluorescence assays to monitor Get3–effector interactions at each stage of targeting. We show that nucleotide and substrate generate differential gradients of interaction energies that drive the ordered interaction of Get3 with successive effectors. These data also provide more molecular details on how the targeting complex is captured and disassembled by the ER receptor and reveal a previously unidentified role for Get4/5 in recycling Get3 from the ER membrane at the end of the targeting reaction. These results provide general insights into how complex protein interaction cascades are coupled to energy inputs in biological systems.
Comparison of the effects of ANF 99–126 and ANF 103–126 on captopril‐induced renin release in man

objective The aim was to examine the effects of atrial natriuretic factor (ANF) 99–126 and ANF 103–126, an N‐terminal shortened analogue of the peptide, on the plasma renin activity response to captopril, an inhibitor of angiotensin‐converting enzyme