Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma

The RAS/RAF/MEK/ERK pathway has been reported to be activated in over 80% of all cutaneous melanomas, making it the focus of many scientific studies in the melanoma field. Discoveries of mutations and aberrant expression of components in this cascade, in particular, BRAF and NRAS render a deeper understanding of the mechanisms responsible for oncogenesis and provide new therapeutic strategies for this deadly disease. This review starts with a comprehensive discussion on the role of this pathway in initiation and progress of melanoma. Mechanistically, mutated BRAF and NRAS exert most of the oncogenic effects through the activation of the MAPK pathway, which both drive the uncontrolled growth of melanoma cells and regulate the cell survival. In a subsequent section, clinical efficacy of targeted small‐molecule inhibitors is highlighted. BRAF‐targeted therapies (e.g., vemurafenib, dabrafenib) have showed impressive results in systemic therapy for melanoma harboring activating BRAF V600E mutations. MEK inhibitors show limited activity in phase I trials, and inhibitors directly targeting mutated NRAS, to date, have not been realized. Furthermore, the emerging mechanisms underlying both intrinsic and acquired drug resistance as well as approaches to prevent or abrogate the onset of therapeutic escape are addressed. Finally, the promising vistas and major challenges involving small‐molecule inhibitors targeting this MAPK pathway in melanoma therapy are briefly discussed. It can be envisaged that disseminated melanoma is no longer such a bleak prognosis in future given the research and development of new signal transduction inhibitors based on our evolving understanding of melanoma genetics and intracellular signaling. © 2013 IUBMB Life, 65(9):748–758, 2013
Assessing the Properties of the WHOQOL-Pain: Quality of Life of Chronic Low Back Pain Patients During Treatment

ObjectivesAssessing subjective, patient-reported outcomes such as quality of life (QoL) is essential to health care research. This study aimed to assess the properties of a QoL measure relating to pain and discomfort: the WHOQOL-Pain. MethodChronic low back pain patients (n=133) completed the WHOQOL-Pain, SF-12, and short-form McGill Pain Questionnaire before treatment started and again 2-4 weeks later. Of these, 76 received a lumbar epidural steroid injection, and 57 were waiting to receive treatment. ResultsOverall, there was no significant difference in effect of either epidural injections or no treatment on bringing about an improvement to QoL overtime. Moderate effect sizes were found for 5 facets including pain relief and uncertainty. Small effect sizes were found for 7 facets including vulnerability, fear and worry, anger and frustration. Larger effect sizes were found for those reporting the most improvement in pain. The waiting group reported no significant changes to QoL but small changes for uncertainty. Three of the four new facets were sensitive to change and test-retest reliability (stability) was confirmed in three. DiscussionAlthough this study was not designed to test treatment effectiveness, the WHOQOL-Pain enables patients to report changes to important aspects of QoL during many diverse interventions for relieving pain.
ODS – modified TiO2 nanoparticles for the preparation of self-cleaning superhydrophobic coating

Rolling water drops takes off dust particles from lotus leaf showing self-cleaning performance. Self-cleaning effect has great importance in industry as well as in daily life. The present paper describes the preparation of self-cleaning superhydrophobic coating through simple and low cost dip coating technique. The prepared superhydrophobic surface enact as lotus leaf. Firstly TiO2 nanoparticles were dispersed in ethanol and different concentration of octadecyltrichlorosilane (ODS) was added in TiO2 dispersion. The effect of number of deposition layer on the wettability of the coating was studied. The coating prepared from five deposition layers showed contact angle higher than 150° and sliding angle less than 10°. The superhydrophobicity increases with increasing concentration of ODS. The hierarchical rough morphology which is preferable for superhydrophobicity was obtained. The prepared coatings were stable against water jet impact and showed repellent towards colored and muddy water. Such superhydrophobic coating can find enormous scope in self-cleaning application.Rolling water drops takes off dust particles from lotus leaf showing self-cleaning performance. Self-cleaning effect has great importance in industry as well as in daily life. The present paper describes the preparation of self-cleaning superhydrophobic coating through simple and low cost dip coating technique. The prepared superhydrophobic surface enact as lotus leaf. Firstly TiO2 nanoparticles were dispersed in ethanol and different concentration of octadecyltrichlorosilane (ODS) was added in TiO2 dispersion. The effect of number of deposition layer on the wettability of the coating was studied. The coating prepared from five deposition layers showed contact angle higher than 150° and sliding angle less than 10°. The superhydrophobicity increases with increasing concentration of ODS. The hierarchical rough morphology which is preferable for superhydrophobicity was obtained. The prepared coatings were stable against water jet impact and showed repellent towards colored and muddy water. Such superhydropho.
STIM1/Orai1, ICRAC, and endothelial SOC.

To the Editor: Store-operated calcium (Ca2+) entry (SOCE) is an evolutionarily conserved pathway of regulated Ca2+ entry into cells whereby the depletion of Ca2+ from internal stores signals the activation of plasma membrane SOC channels.1,2 Nonselective canonical transient receptor potential channel (TRPC) proteins were investigated as potential components of SOC channels in mammals. However, the resulting literature offer no consensus among investigators, and the role of TRPCs in encoding SOC remains a contentious issue.2 In our recent study,3 we challenged the role of TRPCs in endothelial cell (EC) SOCE by showing evidence for I CRAC in ECs encoded by STIM1 and Orai1 independently of TRPC1 and TRPC4. In a letter to Circulation Research ,4 Beech pointed out the discrepancies between previously published data and ours and contended: (1) “ that although the biophysical properties of the I CRAC recorded in divalent-free (DVF) solutions are convincing, its small size in the presence of extracellular Ca 2 + and intracellular BAPTA makes its existence uncertain and that observation of current with BAPTA in the pipette is not proof that it is store-operated ”; and (2) we “ failed to provide confidence for the knockdown of TRPC1 . ” We reject these contentions and maintain that I CRAC encoded by STIM1/Orai1 accounts for EC SOCE based on the following evidence: First, it has been clearly established that I CRAC can be activated to the same extent with any means that deplete the stores; these include: BAPTA or inositol-1,4,5-trisphosphate (IP3) dialysis through the pipette; SERCA inhibitors or ionomycin applied to the bath; sensitizing IP3 receptors to …
Soil-Plant Transfer of Polychlorinated Dibenzo-p-dioxins and Dibenzofurans to Vegetables of the Cucumber Family (Cucurbitaceae).

In a preliminary study in fruits of zucchini (Cucurbita pepo L. convar. giromontiina) polychlorinated dibenzopdioxins and dibenzofurans (PCDD/PCDF) concentrations were found which were approximately 2 orders of magnitude higher than in other fruits and vegetables examined. These results formed the basis for field experiments on the uptake of PCDD/PCDF from contaminated soils by zucchini and related plant species (pumpkin and cucumber). The experimental design allowed the discrimination of several uptake pathways and an evaluation of their contribution to the total PCDD/PCDF contamination of the plants. Using two soils with different organic matter content, additional information was obtained on the influence of soil parameters on the soil-plant transfer of PCDD/PCDF. For zucchini and pumpkin (both belonging to the genus Cucurbita), root uptake of PCDD/PCDF and subsequent translocation to the shoots and into the fruits is the main contamination pathway. Cucumber plants (Cucumis sativus L.), by contrast, are mainly contaminated by deposition of airborne PCDD/PCDF and, consequently, show much lower PCDD/PCDF concentrations. The nature of the mechanism responsible for the unexpectedly high soil-plant transfer into plants of the species Cucurbita pepo L. remains to be clarified.
Caterpillar-induced plant volatiles remain a reliable signal for foraging wasps during dual attack with a plant pathogen or non-host insect herbivore.

Plants respond to herbivory with the emission of plant volatiles, which can be used by the herbivores' natural enemies to locate their hosts or prey. In nature, plants are often simultaneously confronted with insect herbivores and phytopathogens, potentially interfering with the attraction of the herbivores' enemies as a result of modifications of the induced volatile blend. Here, we investigated parasitoid (Cotesia glomerata) attraction to volatiles of plants challenged by different attackers, either alone or in combination with Pieris brassicae caterpillars, hosts of C. glomerata. We used a natural system consisting of Brassica nigra plants, eggs and larvae of P. brassicae, Brevicoryne brassicae aphids and the bacterial phytopathogen Xanthomonas campestris pv. campestris. In all cases, parasitoids successfully located host-infested plants, and wasp foraging behaviour was unaffected by the simultaneous presence of a non-host attacker or host eggs. Analysis of the volatile emissions show that the volatile blends of caterpillar-infested treatments were different from those without caterpillars. Furthermore, dually attacked plants could not be separated from those with only caterpillars, regardless of non-host identity, supporting the behavioural data. Our results suggest that, in this system, indirect plant defences may be more resistant to interference than is generally assumed, with volatiles induced during dual attack remaining reliable indicators of host presence for parasitoids.
Application of wavelets to improvement of defects visibility in active thermography

Detecting defects in adhesively bonded joints using active thermography methods is very promising NDT method. One of the important issue in active thermography is processing of IR image sequence in order to improve defects visibility and detectability. The Wavelet Transform is one of the powerful signal and image processing tool which can be applied to infrared images gathered during active thermography tests. Application of wavelet transform requires to set optimal transform parameters like wavelet type and decomposition level. In the article results of application of wavelet transform to processing of active thermography data were presented. During the research focused on application of wavelets to improve of visibility of defects of adhesively bonded joints.
Maternal Smoking During Pregnancy and Early Child Outcomes

We estimate the harm from smoking during pregnancy upon child birth outcomes, using a rich dataset on a cohort of mothers and their births. We exploit a fixed effects approach to disentangle the correlation between smoking and birth weight from the causal effect. We find that, despite a detailed set of controls for maternal traits, around one-third of the harm from smoking is explained by unobservable traits of the mother. Smoking tends to reduce birth weight by 1.7%, but has no significant effect on the probability of having a low birth weight child, pre-term gestation or weeks of gestation. Exploring heterogeneity in the effect on birth weight, it is mothers who smoke for the 9 months of gestation that suffer the harm, whereas there is an insignificant effect for mothers who chose to quit by month 5. Additionally, there is evidence of potential complementarity in investment of human capital, as the impact on birth weight of smoking is much greater for low educated mothers, even controlling for the quantity of cigarettes they smoke. We suggest policy should target the low educated mothers, offering a more holistic approach to improving child health, as quitting smoking is only half of the battle
Modeling, simulating, and enacting complex organizational processes: a life cycle approach

I describe our approach and mechanisms to support the engineering of organiza tional processes throughout their life cycle I describe our current understanding of what activities are included in the process life cycle I then go on to describe our ap proach computational mechanisms and experiences in supporting many of these life cycle activities as well as compare it to other related e orts Along the way I present examples drawn from a current study aimed at modeling analyzing and integrating an order ful llment process in a product development organization To appear in Simulating Organizations Computational Models of Institutions and Groups K Carley L Gasser and M Prietula eds AAAI Press MIT Press
A computer vision framework for eye gaze tracking

Eye gaze tracking (EGT) allows us to estimate the direction of gaze and the point of regard. This technique has been successfully used as a pointing device in computer interfaces for people with disabilities, but significant technological advances are still required to make EGT appropriate to be used in general computer interfaces. In order to improve the EGT technology, a testbed where new devices and algorithms can be evaluated must be defined. We present a survey of the methods used for EGT, and organize them into a computer vision framework, that we use to support the development and evaluation of new techniques. As an example of application of the framework, the calibration function used in the EGT developed in our laboratory is tested, and the results show the precision of the method. Higher accuracy of the testing results is achieved using synthetic images generated by ray tracing, from a physically based model of the eye.
Circular RNA circMTO1 acts as the sponge of microRNA‐9 to suppress hepatocellular carcinoma progression

Noncoding RNAs play important roles in cancer biology, providing potential targets for cancer intervention. As a new class of endogenous noncoding RNAs, circular RNAs (circRNAs) have been recently identified in cell development and function, and certain types of pathological responses, generally acting as a microRNA (miRNA) sponge to regulate gene expression. Identifying the deregulated circRNAs and their roles in cancer has attracted much attention. However, the expression profile and function of circRNAs in human hepatocellular carcinoma (HCC) remain to be investigated. Here, we analyzed the expression profile of human circRNAs in HCC tissues and identified circMTO1 (mitochondrial translation optimization 1 homologue; hsa_circRNA_0007874/hsa_circRNA_104135) as one circRNA significantly down‐regulated in HCC tissues. HCC patients with low circMTO1 expression had shortened survival. By using a biotin‐labeled circMTO1 probe to perform RNA in vivo precipitation in HCC cells, we identified miR‐9 as the circMTO1‐associated miRNA. Furthermore, silencing of circMTO1 in HCC could down‐regulate p21, the target of oncogenic miR‐9, resulting in the promotion of HCC cell proliferation and invasion. In addition, the tumor‐promoting effect of circMTO1 silencing was blocked by miR9 inhibitor. Intratumoral administration of cholesterol‐conjugated circMTO1 small interfering RNA promoted tumor growth in HCC‐bearing mice in vivo. Conclusion: circMTO1 suppresses HCC progression by acting as the sponge of oncogenic miR‐9 to promote p21 expression, suggesting that circMTO1 is a potential target in HCC treatment. The decrease of circMTO1 in HCC tissues may serve as a prognosis predictor for poor survival of patients. (Hepatology 2017;66:1151‐1164).
Elevated level of serum growth differentiation factor 15 is associated with oral leukoplakia and oral squamous cell carcinoma.

BACKGROUND Although molecular mechanism of growth differentiation factor 15 (GDF15) in tumorigenesis of oral squamous cell carcinoma (OSCC) is not clear, the diagnostic and prognostic value of serum GDF15 detection has been noticed. However, serum GDF15 levels in patients with oral leukoplakia and GDF15 as a potential predictive biomarker for response to induction chemotherapy in patients with OSCC have not been reported. METHODS Pretreatment serum GDF15 concentration was detected using an enzyme-linked immunosorbent assay in 30 healthy persons, 24 patients with oral leukoplakia, and 60 patients with OSCC. RESULTS Serum GDF15 concentration was significantly higher in patients with oral leukoplakia and OSCC, compared with healthy controls (F = 13.701, df = 2, P < 0.001). From a diagnostic standpoint, a cutoff value of 346.9 ng/l of serum GDF15 concentration was calculated using receiver operating characteristic curve, with a sensitivity of 0.750, specificity of 0.867, Youden's Index of 0.617, and area under curve of 0.863. From a prognostic standpoint, patients with serum GDF15 concentration <346.9 ng/l had an improved 3-year disease-free survival rate (64.3% vs 56.5%) compared with those above 346.9 ng/l, but the difference was not statistically significant. A decreased concentration of GDF15 (<346.9 ng/l) showed a predictive trend toward an improved response to induction chemotherapy compared with elevated concentration with clinical response rates of 100% and 71.4%, respectively, but the difference was not significant. CONCLUSION Elevated GDF15 level may be not only a diagnostic biomarker for oral leukoplakia, but also a prognostic/predictive biomarker associated with decreased survival and diminished response to induction chemotherapy for patients with OSCC.
Characteristic neutral loss of CH3CHO from Thr-containing sodium-associated peptides.

A characteristic neutral loss of 44 Da is observed in the MS/MS spectra of Thr-containing sodiated peptides. A combination of tandem mass spectrometry and quantum chemical calculations calculated at the B3LYP/6-311G (d, p) level of ab initio theory is used to elucidate this fragmentation pathway. The high resolution mass spectrometry data indicate this neutral loss is acetaldehyde lost from the side chain of Thr rather than CO2. The intensity of this neutral loss can be enhanced when Thr residue is far from the C-terminus and when the C-terminus is esterified as well. The mechanism of the acetaldehyde loss is proposed to adopt a McLafferty-type rearrangement reaction, which involves a proton transfer from the hydroxyl of Thr side chain to its C-terminal neighboring carbonyl oxygen inducing the cleavage of the Ca-Cβ bond. This mechanism is further supported by examining the fragmentation of a [GT(tBu)G + Na](+) peptide derivative and by comparing the product ion spectra of [M + Na-44](+) of [GTGA + Na](+) with [M + Na](+) of [GGGA + Na](+). A similar neutral loss of HCHO can also be detected in Ser-containing peptides. Our computational results reveal that the most stable [GTG + Na](+) ion is present as a tridentate charge-solvated structure and the dissociation leading to the 44 loss is dynamically and energetically favorable.
The puzzle of ambiguity

Montague’s celebrated claim that no “important theoretical difference exists between formal and natural languages” (Montague 1974; 188) implies that ambiguity is not theoretically important, for ambiguity abounds in natural languages, whereas formal languages are unambiguous by design. More generally, the pervasiveness of ambiguity in natural languages seems to be widely regarded as unremarkable. Our objective in this paper is to argue, to the contrary, that the highly ambiguous character of natural languages is surprising, and that the very existence of ambiguity calls for an explanation.
Requirement of neuronal connexin36 in pathways mediating presynaptic inhibition of primary afferents in functionally mature mouse spinal cord

• Reflexes evoked by sensory information from muscles and skin play an important role in controlling muscle activity during movement. • The strength of these reflexes is regulated in part by presynaptic inhibition, a process controlling the release of chemical transmitters from sensory fibres terminating on spinal neurones. • Our study is the first to show that electrical synapses among spinal neurones in young animals are essential for normal operation of processes that presynaptically regulate synaptic transmission between large diameter sensory fibres and spinal cord neurones. • Transgenic mice lacking connexin36, a protein that mediates electrical communication via gap junctions between neurones, suffer a severe impairment of presynaptic inhibition and a similar impairment can be produced in normal mice with drugs that disrupt gap junction function. • The wide distribution of connexin36 in the spinal cord suggests that neuronal gap junctions also play a role in other physiological processes.
A modified harmony search method for wind generator design

The harmony search HS method is an emerging meta-heuristic optimisation algorithm, which has been widely employed to deal with various optimisation problems during the past decade. However, like most of the evolutionary computation techniques, it sometimes suffers from a rather slow search speed, and even fails to find the global optima in an efficient way. In this paper, a new HS method with dual memory, namely DUAL-HS, is proposed and studied. The secondary memory in the DUAL-HS takes advantage of the opposition-based learning OBL to evolve so that the quality of all the harmony memory members can be significantly improved. Optimisation of 25 typical benchmark functions demonstrate that compared with the regular HS method, our DUAL-HS has an enhanced convergence property. The DUAL-HS is further applied for the wind generator design, in which it has also shown a satisfactory optimisation performance.
An unbalance between von Willebrand factor and ADAMTS13 in acute liver failure: Implications for hemostasis and clinical outcome

Emerging evidence supports the concept of a rebalanced hemostatic state in liver disease as a result of a commensurate decline in prohemostatic and antihemostatic drivers. In the present study, we assessed levels and functionality of the platelet‐adhesive protein von Willebrand factor (VWF) and its cleaving protease ADAMTS13 in the plasma of patients with acute liver injury and acute liver failure (ALI/ALF). Furthermore, we explored possible associations between VWF, ADAMTS13, and disease outcome. We analyzed the plasma of 50 patients taken on the day of admission for ALI/ALF. The plasma of 40 healthy volunteers served as controls. VWF antigen levels were highly elevated in patients with ALI/ALF. In contrast, the collagen‐binding activity and the ratio of the VWF ristocetin cofactor activity and VWF antigen was significantly decreased when compared with healthy controls. Also, the proportion of high molecular weight VWF multimers was reduced, despite severely decreased ADAMTS13 levels. In spite of these functional defects, platelet adhesion and aggregation were better supported by plasma of patients with ALI/ALF when compared with control plasma. Low ADAMTS13 activity, but not high VWF antigen, was associated with poor outcome in patients with ALI/ALF as evidenced by higher grades of encephalopathy, higher transplantation rates, and lower survival. VWF or ADAMTS13 levels were not associated with bleeding or thrombotic complications. Conclusion: Highly elevated levels of VWF in plasma of patients with ALI/ALF support platelet adhesion, despite a relative loss of function of the molecule. Furthermore, low ADAMTS13 activity is associated with progressive liver failure in the patient cohort, which might be attributed to platelet‐induced microthrombus formation in the diseased liver resulting from a substantially unbalanced VWF/ADAMTS13 ratio. (Hepatology 2013;58:752–761)