Miracle-dz/UniFAR-FTUs huggingface dataset:
Munc18-1-regulated stage-wise SNARE assembly underlying synaptic exocytosis

Synaptic-soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins couple their stage-wise folding/assembly to rapid exocytosis of neurotransmitters in a Munc18-1-dependent manner. The functions of the different assembly stages in exocytosis and the role of Munc18-1 in SNARE assembly are not well understood. Using optical tweezers, we observed four distinct stages of assembly in SNARE N-terminal, middle, C-terminal, and linker domains (or NTD, MD, CTD, and LD, respectively). We found that SNARE layer mutations differentially affect SNARE assembly. Comparison of their effects on SNARE assembly and on exocytosis reveals that NTD and CTD are responsible for vesicle docking and fusion, respectively, whereas MD regulates SNARE assembly and fusion. Munc18-1 initiates SNARE assembly and structures t-SNARE C-terminus independent of syntaxin N-terminal regulatory domain (NRD) and stabilizes the half-zippered SNARE complex dependent upon the NRD. Our observations demonstrate distinct functions of SNARE domains whose assembly is intimately chaperoned by Munc18-1. DOI: http://dx.doi. org/10.7554/eLife.09580. 001
Comparison of tailored and empiric scan delays for CT angiography of the abdomen.

OBJECTIVE Scan delays for CT angiography of the abdomen are currently individualized by matching a scan delay to the transit time of a test bolus of IV contrast material to the abdominal aorta. We sought to determine whether this procedure improves the extent and uniformity of aortic enhancement when compared with the use of a standard scan delay that is determined empirically. SUBJECTS AND METHODS CT angiography of the upper abdomen (either the entire abdominal aorta or the aorta spanning the length of both kidneys for dedicated renal studies) was obtained in 48 patients who were considered to have normal cardiac function as determined by their referring physicians. Patients were randomized to undergo CT angiography that used either a standard scan delay of 20 or 22 sec (group 1, n = 26) or a tailored scan delay (group 2, n = 22), all other imaging parameters being identical. Tailored delays were determined by measuring contrast transit time to the abdominal aorta with software from the SmartPrep system. For each patient, aortic attenuation was measured at three different anatomic levels, and a lower threshold of 160 H was considered optimal. The number of attenuation values above this threshold, the mean attenuation, and the attenuation changes for each unit length along the abdominal aorta were then compared for the two groups of patients. RESULTS Fifty-eight (74%) of 78 aortic attenuation values in group 1 and 55 (88%) of 69 in group 2 were above 160 H. Mean attenuation values were 192.2 H +/- 8.1 (+/-SE) in group 1 and 199.2 H +/- 10.1 in group 2. These values and the attenuation changes for each unit length along the abdominal aorta-3.7 H/cm +/- 1.7 for group 1 and 2.2 H/cm +/- 2.0 for group 2- were not significantly different. CONCLUSION Tailoring the scan delay for CT angiography of the abdomen in patients considered to have normal cardiac function requires additional IV contrast agent, time, and patient imaging and does not improve the extent or uniformity of aortic enhancement over that obtained with a standard, empiric scan delay.
Existence of Turing Instabilities in a Two-Species Fractional Reaction-Diffusion System

We introduce a two-species fractional reaction-diffusion system to model activator- inhibitor dynamics with anomalous diffusion such as occurs in spatially inhomogeneous media. Con- ditions are derived for Turing-instability induced pattern formation in these fractional activator- inhibitor systems whereby the homogeneous steady state solution is stable in the absence of diffusion but becomes unstable over a range of wavenumbers when fractional diffusion is present. The condi- tions are applied to a variant of the Gierer-Meinhardt reaction kinetics which has been generalized to incorporate anomalous diffusion in one or both of the activator and inhibitor variables. The anoma- lous diffusion extends the range of diffusion coefficients over which Turing patterns can occur. An intriguing possibility suggested by this analysis, which can arise when the diffusion of the activator is anomalous but the diffusion of the inhibitor is regular, is that Turing instabilities can exist even when the diffusion coefficient of the activator exceeds that of the inhibitor.
Peripheral, but Not Central, CB1 Antagonism Provides Food Intake–Independent Metabolic Benefits in Diet-Induced Obese Rats

OBJECTIVE—Blockade of the CB1 receptor is one of the promising strategies for the treatment of obesity. Although antagonists suppress food intake and reduce body weight, the role of central versus peripheral CB1 activation on weight loss and related metabolic parameters remains to be elucidated. We therefore specifically assessed and compared the respective potential relevance of central nervous system (CNS) versus peripheral CB1 receptors in the regulation of energy homeostasis and lipid and glucose metabolism in diet-induced obese (DIO) rats. RESEARCH DESIGN AND METHODS—Both lean and DIO rats were used for our experiments. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR, and euglycemic-hyperinsulinemic clamps were used for insulin sensitivity and glucose metabolism studies. RESULTS—Specific CNS-CB1 blockade decreased body weight and food intake but, independent of those effects, had no beneficial influence on peripheral lipid and glucose metabolism. Peripheral treatment with CB1 antagonist (Rimonabant) also reduced food intake and body weight but, in addition, independently triggered lipid mobilization pathways in white adipose tissue and cellular glucose uptake. Insulin sensitivity and skeletal muscle glucose uptake were enhanced, while hepatic glucose production was decreased during peripheral infusion of the CB1 antagonist. However, these effects depended on the antagonist-elicited reduction of food intake. CONCLUSIONS—Several relevant metabolic processes appear to independently benefit from peripheral blockade of CB1, while CNS-CB1 blockade alone predominantly affects food intake and body weight.
Molecular dynamics and functional studies define a hot spot of crystal contacts essential for PcTx1 inhibition of acid‐sensing ion channel 1a

The spider‐venom peptide PcTx1 is the most potent and selective inhibitor of acid‐sensing ion channel (ASIC) 1a. It has centrally acting analgesic activity and is neuroprotective in rodent models of ischaemic stroke. Understanding the molecular details of the PcTx1 : ASIC1a interaction should facilitate development of therapeutically useful ASIC1a modulators. Previously, we showed that several key pharmacophore residues of PcTx1 reside in a dynamic β‐hairpin loop; conclusions confirmed by recent crystal structures of the complex formed between PcTx1 and chicken ASIC1 (cASIC1). Numerous peptide : channel contacts were observed in these crystal structures, but it remains unclear which of these are functionally important.
Long-range integrable spin chains and plane-wave matrix theory

Quantum spin chains arise naturally from perturbative large-N field theories and matrix models. The Hamiltonian of such a model is a long-range deformation of nearest-neighbour type interactions. Here, we study the most general long-range integrable spin chain with spins transforming in the fundamental representation of . We derive the Hamiltonian and the corresponding asymptotic Bethe ansatz at the leading four perturbative orders with several free parameters. Furthermore, we propose Bethe equations for all orders and identify the moduli of the integrable system. We finally apply our results to plane-wave matrix theory and show that the Hamiltonian in a closed sector is not of this form and therefore not integrable beyond the first perturbative order. This also implies that the complete model is not integrable.
Effects of Simian Virus 40 Large and Small Tumor Antigens on Mammalian Target of Rapamycin Signaling: Small Tumor Antigen Mediates Hypophosphorylation of eIF4E-Binding Protein 1 Late in Infection

ABSTRACT We report that late in a simian virus 40 (SV40) infection in CV-1 cells, there are significant decreases in phosphorylations of two mammalian target of rapamycin (mTOR) signaling effectors, the eIF4E-binding protein (4E-BP1) and p70 S6 kinase (p70S6K). The hypophosphorylation of 4E-BP1 results in 4E-BP1 binding to eIF4E, leading to the inhibition of cap-dependent translation. The dephosphorylation of 4E-BP1 is specifically mediated by SV40 small t antigen and requires the protein phosphatase 2A binding domain but not an active DnaJ domain. Serum-starved primary African green monkey kidney (AGMK) cells also showed decreased phosphorylations of mTOR, 4E-BP1, and p70S6K at late times in infection (48 h postinfection [hpi]). However, at earlier times (12 and 24 hpi), in AGMK cells, phosphorylated p70S6K was moderately increased, correlating with a significant increase in phosphorylation of the p70S6K substrate, ribosomal protein S6. Hyperphosphorylation of 4E-BP1 at early times could not be determined, since hyperphosphorylated 4E-BP1 was present in mock-infected AGMK cells. Elevated levels of phosphorylated eIF4G, a third mTOR effector, were detected in both CV-1 and AGMK cells at all times after infection, indicating that eIF4G phosphorylation was induced throughout the infection and unaffected by small t antigen. The data suggest that during SV40 lytic infection in monkey cells, the phosphorylations of p70S6K, S6, and eIF4G are increased early in the infection (12 and 24 hpi), but late in the infection (48 hpi), the phosphorylations of mTOR, p70S6K, and 4E-BP1 are dramatically decreased by a mechanism mediated, at least in part, by small t antigen.
The unique determination of neuronal currents in the brain via magnetoencephalography

The problem of determining the neuronal current inside the brain from measurements of the induced magnetic field outside the head is discussed under the assumption that the space occupied by the brain is approximately spherical. By inverting the Geselowitz equation, the part of the current which can be reconstructed from the measurements is precisely determined. This actually consists of only certain moments of one of the two functions specifying the tangential part of the current. The other function specifying the tangential part of the current as well as the radial part of the current is completely arbitrary. However, it is also shown that with the assumption of energy minimization, the current can be reconstructed uniquely. A numerical implementation of this unique reconstruction is also presented.
Paradoxical Activation of T Cells via Augmented ERK Signaling Mediated by a RAF Inhibitor

Callahan and colleagues show that RAF inhibitors can potentiate T-cell activation by increasing T-cell expansion and ERK signaling, and when combined with CTLA-4 blockade show superior tumor control in two transplantable mouse tumor models. RAF inhibitors selectively block extracellular signal–regulated kinase (ERK) signaling in BRAF-mutant melanomas and have defined a genotype-guided approach to care for this disease. RAF inhibitors have the opposite effect in BRAF wild-type tumor cells, where they cause hyperactivation of ERK signaling. Here, we predict that RAF inhibitors can enhance T-cell activation, based on the observation that these agents paradoxically activate ERK signaling in BRAF wild-type cells. To test this hypothesis, we have evaluated the effects of the RAF inhibitor BMS908662 on T-cell activation and signaling in vitro and in vivo. We observe that T-cell activation is enhanced in a concentration-dependent manner and that this effect corresponds with increased ERK signaling, consistent with paradoxical activation of the pathway. Furthermore, we find that the combination of BMS908662 with cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockade in vivo potentiates T-cell expansion, corresponding with hyperactivation of ERK signaling in T cells detectable ex vivo. Finally, this combination demonstrates superior antitumor activity, compared with either agent alone, in two transplantable tumor models. This study provides clear evidence that RAF inhibitors can modulate T-cell function by potentiating T-cell activation in vitro and in vivo. Paradoxical activation of ERK signaling in T cells offers one mechanism to explain the enhanced antitumor activity seen when RAF inhibitors are combined with CTLA-4 blockade in preclinical models. Cancer Immunol Res; 2(1); 70–79. ©2013 AACR.
Learning Laparoscopic-Assisted Hysterectomy

OBJECTIVE: The aim of this study was to evaluate the factors considered for proficiency and to estimate the number of procedures needed to achieve competence in laparoscopic-assisted vaginal hysterectomy in a teaching hospital. METHODS: The length of the learning curve, duration of surgery, change of hemoglobin (in grams per liter), conversion rate, and intra- and postoperative complications were evaluated. Cases were analyzed according to the order for the individual surgeon. RESULTS: Thirty-three surgeons performed 929 laparoscopic-assisted vaginal hysterectomies during the study period. Analyzing the duration of surgery and rate of complications, we decided on a cutoff of 30 cases. Eight surgeons with more than 30 cases performed 668 laparoscopic-assisted vaginal hysterectomies. Their initial 30 cases (group A, the first 30 cases) were compared with their subsequent cases (group B, cases 31 and after). Patient age, body mass index, and uterine weight did not differ between the groups. The intraoperative complication rate dropped from 4.2% to 0.5% (P = .001), hemoglobin drop decreased from −0.8 ± 0.9 g/L to −0.5 ± 1.0 g/L (P = .002), and postoperative complications dropped from 12.9% to 7.0% (P = .017). The duration of surgery was also shorter (148.8 ± 45.4 minutes versus 125.1 ± 46.5 minutes), but this difference was taken from the results of 1 surgeon. CONCLUSION: A learning experience of 30 laparoscopic-assisted vaginal hysterectomies was necessary in our institution to reach a low level of complications. Duration of the surgical procedure was not an adequate study endpoint to assess a learning effect. LEVEL OF EVIDENCE: II-3
Psychology Research and Behavior Management Dovepress the Association between Self-injurious Behaviors and Autism Spectrum Disorders

A key area of concern in children with autism spectrum disorders (ASDs) are self-injurious behaviors (SIBs). These are behaviors that an individual engages in that may cause physical harm, such as head banging, or self-biting. SIBs are more common in children with ASD than those who are typically developing or have other neurodevelopmental disabilities. Therefore, it is important that clinicians who work with children with ASD have a solid understanding of SIB. The purpose of this paper is to review the research on the epidemiology of SIB in children with ASD, factors that predict the presence of SIB in this population, and the empirically supported behavioral treatments available.
Using word alignments to assist computer-aided translation users by marking which target-side words to change or keep unedited

This paper explores a new method to improve computer-aided translation (CAT) systems based on translation memory (TM) by using pre-computed word alignments between the source and target segments in the translation units (TUs) of the user’s TM. When a new segment is to be translated by the CAT user, our approach uses the word alignments in the matching TUs to mark the words that should be changed or kept unedited to transform the proposed translation into an adequate translation. In this paper, we evaluate different sets of alignments obtained by using GIZA++. Experiments conducted in the translation of Spanish texts into English show that this approach is able to predict which target words have to be changed or kept unedited with an accuracy above 94% for fuzzy-match scores greater or equal to 60%. In an appendix we evaluate our approach when new TUs (not seen during the computation of the word-alignment models) are used.
VLT and ACS Observations of RDCS J1252.9–2927: Dynamical Structure and Galaxy Populations in a Massive Cluster at z = 1.237

We present results from an extensive spectroscopic survey, carried out with VLT FORS, and from an extensive multiwavelength imaging data set from the HST Advanced Camera for Surveys and ground-based facilities, of the cluster of galaxies RDCS J1252.9-2927. We have spectroscopically confirmed 38 cluster members in the redshift range 1.22 < z < 1.25. A cluster median redshift of z = 1.237 and a rest-frame velocity dispersion of 747 km s-1 are obtained. Using the 38 confirmed redshifts, we were able to resolve, for the first time at z > 1, kinematic structure. The velocity distribution, which is not Gaussian at the 95% confidence level, is consistent with two groups that are also responsible for the projected east-west elongation of the cluster. The groups are composed of 26 and 12 galaxies with velocity dispersions of 486 and 426 km s-1, respectively. The elongation is also seen in the intracluster gas and the dark matter distribution. This leads us to conclude that RDCS J1252.9-2927 has not yet reached a final virial state. We extend the analysis of the color-magnitude diagram of spectroscopic members to more than 1 Mpc from the cluster center. The scatter and slope of non-[O II]-emitting cluster members in the near-IR red sequence is similar to that seen in clusters at lower redshift. Furthermore, most of the galaxies with luminosities greater than ~K + 1.5 do not show any [O II], indicating that these more luminous, redder galaxies have stopped forming stars earlier than the fainter, bluer galaxies. Our observations provide detailed dynamical and spectrophotometric information on galaxies in this exceptional high-redshift cluster, delivering an in-depth view of structure formation at this epoch only 5 Gyr after the big bang.
Mediation of Autophagic Cell Death by Type 3 Ryanodine Receptor (RyR3) in Adult Hippocampal Neural Stem Cells

Cytoplasmic Ca2+ actively engages in diverse intracellular processes from protein synthesis, folding and trafficking to cell survival and death. Dysregulation of intracellular Ca2+ levels is observed in various neuropathological states including Alzheimer’s and Parkinson’s diseases. Ryanodine receptors (RyRs) and inositol 1,4,5-triphosphate receptors (IP3Rs), the main Ca2+ release channels located in endoplasmic reticulum (ER) membranes, are known to direct various cellular events such as autophagy and apoptosis. Here we investigated the intracellular Ca2+-mediated regulation of survival and death of adult hippocampal neural stem (HCN) cells utilizing an insulin withdrawal model of autophagic cell death (ACD). Despite comparable expression levels of RyR and IP3R transcripts in HCN cells at normal state, the expression levels of RyRs—especially RyR3—were markedly upregulated upon insulin withdrawal. While treatment with the RyR agonist caffeine significantly promoted the autophagic death of insulin-deficient HCN cells, treatment with its inhibitor dantrolene prevented the induction of autophagy following insulin withdrawal. Furthermore, CRISPR/Cas9-mediated knockout of the RyR3 gene abolished ACD of HCN cells. This study delineates a distinct, RyR3-mediated ER Ca2+ regulation of autophagy and programmed cell death in neural stem cells. Our findings provide novel insights into the critical, yet understudied mechanisms underlying the regulatory function of ER Ca2+ in neural stem cell biology.
A 3D Conjugate Approach for Analysing a Double-Walled Effusion-Cooled Turbine Blade

A double-wall cooling scheme combined with effusion cooling offers a practical approximation to transpiration cooling which in turn presents the potential for very high cooling effectiveness. The use of the conventional conjugate CFD for the double-wall blade can be computationally expensive and this approach is therefore less than ideal in cases where only the preliminary results are required. This paper presents a computationally efficient numerical approach for analysing a double-wall effusion cooled gas turbine blade. An existing correlation from the literature was modified and used to represent the two-dimensional distribution of film cooling effectiveness. The internal heat transfer coefficient was calculated from a validated conjugate analysis of a wall element representing an element of the aerofoil wall and the conduction through the blade solved using a finite element code in ANSYS*. The numerical procedure developed has permitted a rapid evaluation of the critical parameters including; film cooling effectiveness, blade temperature distribution (and hence metal effectiveness) as well as coolant mass flow consumption. Good agreement was found between the results from this study and that from literature. This paper shows that a straightforward numerical approach that combines an existing correlation for film cooling from the literature with a conjugate analysis of a small wall element can be used to quickly predict the blade temperature distribution and other crucial blade performance parameters.
A Novel Ion Channel Formed by Interaction of TRPML3 with TRPV5

TRPML3 and TRPV5 are members of the mucolipin (TRPML) and TRPV subfamilies of transient receptor potential (TRP) cation channels. Based on sequence similarities of the pore forming regions and on structure-function evidence, we hypothesized that the pore forming domains of TRPML and TRPV5/TRPV6 channels have similarities that indicate possible functional interactions between these TRP channel subfamilies. Here we show that TRPML3 and TRPV5 associate to form a novel heteromeric ion channel. This novel conductance is detectable under conditions that do not activate either TRPML3 or TRPV5. It has pharmacological similarity with TRPML3 and requires functional TRPML3 as well as functional TRPV5. Single channel analyses revealed that TRPML3 and TRPV5 heteromers have different features than the respective homomers, and furthermore, that they occur in potentially distinct stoichiometric configurations. Based on overlapping expression of TRPML3 and TRPV5 in the kidney and the inner ear, we propose that TRPML3 and TRPV5 heteromers could have a biological function in these organs.
International Conference on Information Systems ( ICIS ) 1-1-2010 Social Influence and Willingness to Pay for Online Video Games

Social influence is an important factor in guiding individual behavior, including purchase decisions. The online gaming industry has demonstrated itself to be one of the most successful business sectors to integrate the Internet into its business models. The purpose of the study is to investigate the influence an individual’s social environment has on willingness-to-pay a subscription fee for an online video game. Specifically, social influence is conceptualized as occurring on three levels within an individual’s social environment: the micro-, meso-, and macro-levels. Using a survey research methodology, this study examines the effects that these influences have on expected benefit, willingness-to-pay, and each other.