Miracle-dz/UniFAR-FTUs huggingface dataset:
Interrogation of SLFN11 in pediatric sarcomas uncovers an unexpected biological role and a novel therapeutic approach to overcoming resistance to replicative stress

Pediatric sarcomas represent a heterogeneous group of malignancies that exhibit variable response to DNA damaging chemotherapy. Schlafen family member 11 protein (SLFN11) increases sensitivity to replicative stress, and SLFN11 gene silencing has been implicated as a common mechanism of drug resistance in tumors in adults. We found SLFN11 to be widely expressed in our cohort of pediatric sarcomas. In sarcoma cell lines, protein expression strongly correlated with response to the PARP inhibitor talazoparib (TAL) and the topoisomerase I inhibitor irinotecan (IRN), with SLFN11 knockout resulting in significant loss of sensitivity in vitro and in vivo. However, SLFN11 expression was not associated with favorable outcomes in a retrospective analysis of our patient cohort; instead, the protein was retained and promoted tumor growth and evasion. Furthermore, we show that pediatric sarcomas develop resistance to TAL and IRN through impaired intrinsic apoptosis, and that resistance can be reversed by selective inhibition of BCL-XL. Statement of Significance The role of SLFN11 in pediatric sarcomas has not been thoroughly explored. In contrast to its activity in adult tumors, SLFN11 did not predict favorable outcomes in pediatric patients, was not silenced, and promoted tumor growth. Resistance to replicative stress in SLFN11-expressing sarcomas was reversed by selective inhibition of BCL-XL.
ACAULIS5 Is Required for Cytokinin Accumulation and Function During Secondary Growth of Populus Trees

In the primary root and young hypocotyl of Arabidopsis, ACAULIS5 promotes translation of SUPPRESSOR OF ACAULIS51 (SAC51) and thereby inhibits cytokinin biosynthesis and vascular cell division. In this study, the relationships between ACAULIS5, SAC51 and cytokinin biosynthesis were investigated during secondary growth of Populus stems. Overexpression of ACAULIS5 from the constitutive 35S promoter in hybrid aspen (Populus tremula × Populus tremuloides) trees suppressed the expression level of ACAULIS5, which resulted in low levels of the physiologically active cytokinin bases as well as their direct riboside precursors in the transgenic lines. Low ACAULIS5 expression and low cytokinin levels of the transgenic trees coincided with low cambial activity of the stem. ACAULIS5 therefore, contrary to its function in young seedlings in Arabidopsis, stimulates cytokinin accumulation and cambial activity during secondary growth of the stem. This function is not derived from maturing secondary xylem tissues as transgenic suppression of ACAULIS5 levels in these tissues did not influence secondary growth. Interestingly, evidence was obtained for increased activity of the anticlinal division of the cambial initials under conditions of low ACAULIS5 expression and low cytokinin accumulation. We propose that ACAULIS5 integrates auxin and cytokinin signaling to promote extensive secondary growth of tree stems.
Identification of New Leaf Rust Resistance Loci in Wheat and Wild Relatives by Array-Based SNP Genotyping and Association Genetics

Leaf rust caused by Puccinia triticina is the most widespread rust disease of wheat. As pathogen populations are constantly evolving, identification of novel sources of resistance is necessary to maintain disease resistance and stay ahead of this plant-pathogen evolutionary arms race. The wild genepool of wheat is a rich source of genetic diversity, accounting for 44% of the Lr genes identified. Here we performed a genome-wide association study (GWAS) on a diverse germplasm of 385 accessions, including 27 different Triticum and Aegilops species. Genetic characterization using the wheat 90 K array and subsequent filtering identified a set of 20,501 single nucleotide polymorphic (SNP) markers. Of those, 9,570 were validated using exome capture and mapped onto the Chinese Spring reference sequence v1.0. Phylogenetic analyses illustrated four major clades, clearly separating the wild species from the T. aestivum and T. turgidum species. GWAS was conducted using eight statistical models for infection types against six leaf rust isolates and leaf rust severity rated in field trials for 3–4 years at 2–3 locations in Canada. Functional annotation of genes containing significant quantitative trait nucleotides (QTNs) identified 96 disease-related loci associated with leaf rust resistance. A total of 21 QTNs were in haplotype blocks or within flanking markers of at least 16 known Lr genes. The remaining significant QTNs were considered loci that putatively harbor new Lr resistance genes. Isolation of these candidate genes will contribute to the elucidation of their role in leaf rust resistance and promote their usefulness in marker-assisted selection and introgression.
Achieving Sustainable Development Goals (SDGs) in Sub-Saharan Africa (SSA): A Conceptual Review of Normative Economics Frameworks

Background: The health status of the Sub-Saharan African (SSA) countries is well below that of the rest of the world. Coupled with low per capita income, these countries have agreed and committed themselves to raising their health status equitable standard by addressing United Nations (UN) Sustainability Development Goal number 3 (SDG3) by 2030. Addressing SDG3 requires increased and equitable funding for universal health coverage, healthcare infrastructure, efficient resource allocation, improved priority setting, reduction in corruption, and other strategies. However, what is urgently needed to improve priority setting processes or meaningful health system reform, among other things. There is therefore a need for the exploration of the economic and non-economic (which includes social justice) explicit criteria that ought to form the normative framework for Decision Making. These explicit criteria include efficiency, burden of disease, equality (strict egalitarianism), equity, and explicit criteria. Methods: The ultimate aim was to identify explicit values/principles/criteria that can be used to formulate an ideal normative framework to be used to guide decision Making so as to improve SDG3 in SSA. We synthesized selected literature on the normative frameworks for priority setting processes in health in SSA was undertaken, and the explicit criteria which, ought to guide these frameworks were identified. The form of the Social Welfare function and its principles was identified. Results and Conclusions: The framework and its explicit criteria for priority setting in the SSA countries that ought to be adopted in order to improve their SDG3 was identified—Non-Welfarist framework. This framework allows utility, health and other important social values/attributes/principles to enter the normative SWF. It is argued that such a framework ought to be specified empirically and concurrently by the decision-makers and members of the community representatives. Community representatives ought to be recognized as legitimate claimants of the resources determined, and should therefore be allowed to have a role in specifying the arguments in the SWF and what weights to be attached to the stated arguments. This implies that the selection of options in decision-making should focus on maximizing benefit and minimizing the opportunities forgone as stated in the framework.
Consistency of SVDQuartets and Maximum Likelihood for Coalescent-based Species Tree Estimation

Numerous methods for inferring species-level phylogenies under the coalescent model have been proposed within the last 20 years, and debates continue about the relative strengths and weaknesses of these methods. One desirable property of a phylogenetic estimator is that of statistical consistency, which means intuitively that as more data are collected, the probability that the estimated tree has the same topology as the true tree goes to 1. To date, consistency results for species tree inference under the multispecies coalescent have been derived only for summary statistics methods, such as ASTRAL and MP-EST. These methods have been found to be consistent given true gene trees, but may be inconsistent when gene trees are estimated from data for loci of finite length (Roch et al., 2019). Here we consider the question of statistical consistency for four taxa for SVDQuartets for general data types, as well as for the maximum likelihood (ML) method in the case in which the data are a collection of sites generated under the multispecies coalescent model such that the sites are conditionally independent given the species tree (we call these data Coalescent Independent Sites (CIS) data). We show that SVDQuartets is statistically consistent for all data types (i.e., for both CIS data and for multilocus data), and we derive its rate of convergence. We additionally show that ML is consistent for CIS data under the JC69 model, and discuss why a proof for the more general multilocus case is difficult. Finally, we compare the performance of maximum likelihood and SDVQuartets using simulation for both data types.
Effect of Chronic Alcohol Consumption on Nutritional Composition of Breast Milk: An Experimental Study

The aim of the present study was to analyze the nutritional effects of alcohol consumption in the form of distilled and fermented beverages, together with a diet made up of habitual foods of northeastern Brazil, on the composition of breast milk. Sixty Wistar rats were divided into five experimental groups, and all received a balanced diet of beans, rice, chicken, cassava flour and soybean oil (18% protein content), associated to different liquids in accordance with the following experimental groups: Control Group (CG) – distilled water; Alcohol Group (AG) – 5% hydroalcoholic solution; Peer-Fed Alcohol Group (PFAG) – maltodextrin solution replacing calories from alcohol; Beer Group (BG) – beer (5% ethanol v/v); Peer-Fed Beer Group (PFBG) - maltodextrin solution replacing calories from beer. On the 12th day of lactation, breast milk was withdrawn for the analysis of protein, carbohydrates, total lipids, fraction of triglyceride, sodium and potassium. The Mann-Whitney test was used for the statistical analysis, with the level of significance set at 5% (p < 0.05). There was an increase in potassium content in the breast milk in the AG and an increase in lactose content in the breast milk in the BG. It may be concluded that the use of alcoholic beverages, even those with low ethanol content, during lactation can cause serious alterations in the metabolism of mothers, altering the composition of breast milk and possibly compromising the normal development of newborns
Cladosporium omanense, a new endophytic species from Zygophyllum coccineum in Oman

The genus Cladosporium is cosmopolitan in distribution and can be isolated from various sources including plants as endophytes. A strain of Cladosporium was isolated from living leaves of Zygophyllum coccineum in a desert habitat in Oman. Phylogenetic analysis based on the combined internal transcribed spacer (ITS), partial translation elongation factor 1-alpha (TEF) and partial actin (ACT) sequence data shows that this is a novel species, which groups with Cladosporium sphaerospermum complex. The new species is introduced as Cladosporium omanense and is described, illustrated and compared with other known species in the genus. Cladosporium omanense differs from its phylogenetically related species C. endophyticum by its fast growing colonies, longer macronematous and micronematous conidiophores, thickened-walled conidia with conspicuously protuberant shrivelling surface ornamentations.
The Development and Assessment of Modified Fagerstrom Test for Nicotine Dependence Scale among Malaysian Single Electronic Cigarette Users

Background: The Fagerstrom test for nicotine dependence (FTND) is the most widely used scale for assessing nicotine dependence on conventional tobacco cigarettes (TCGs). But the FTND does not evaluate the subject’s nicotine dependence to electronic cigarette (EC). Objective: The aim of this study was to develop and assess an equivalent modified FTND scale that measures the nicotine dependency via EC. Materials and Methods: The investigator developed the equivalent modified FTND scale that scores identical to the original scale, that is, 0–10. The developed scale piloted among 15 EC single users, that is, use only EC verified by carbon monoxide (CO) level of <8 ppm. The assessment of the scale was done among 69 EC single users and observed for 1 year to determine their nicotine status. Results: The modified scale revealed an acceptable Cronbach α value of 0.725. Further test–retest reliability of the scale showed a satisfactory Spearman’s rank correlation coefficient value of 0.730 (P > 0.05). A 1-year observation showed that of 69 single users, 11 single users completely stopped nicotine intake, 24 remained as EC single users, 15 shifted to dual-use, and 19 relapsed to TCG. Surprisingly, the EC users who completely stopped nicotine intake after 1 year had a low average nicotine dependence value of 3 that was measured by the modified FTND scale at the baseline. Conclusion: The modified FTND scale precisely identifies the physical dependence to nicotine via EC. Therefore, as per this study results the modified FTND scale can be applied in any EC-related studies to assess nicotine dependency via EC.
Molecular Docking Study of Naturally Derived Flavonoids with Antiapoptotic BCL-2 and BCL-XL Proteins toward Ovarian Cancer Treatment

The naturally derived flavonoids are well known to have anticarcinogenic effects. Flavonoids could be an alternative strategy for ovarian cancer treatment, due to existing platinum-based drugs are reported to develop resistance with low survival rates. Inhibition of antiapoptotic proteins, namely B-cell lymphoma (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl), is the key target to stimulate apoptosis process in cancer cells. This study aimed to determine the binding interaction of five naturally derived flavonoids (biochanin A, myricetin, apigenin, galangin, and fisetin) with potential antiapoptotic target proteins (Bcl-2 and Bcl-xl). The molecular docking study was conducted using AutoDock Vina program. The binding affinity and the presence of hydrogen bonds between the flavonoids and target proteins were predicted. Our findings showed that all the flavonoids showed better binding affinity with Bcl-xl than that of Bcl-2 proteins. The highest binding affinity was recorded in fisetin–Bcl-xl protein complex (−8.8 kcal/mol). Meanwhile, the other flavonoids docked with Bcl-xl protein showed binding affinities, ranging from –8.0 to –8.6 kcal/mol. A total of four hydrogen bonds, four hydrophobic contacts, and one electrostatic interaction were detected in the docked fisetin–Bcl-xl complex, explaining its high binding affinity with Bcl-xl. The present results indicate that all flavonoids could potentially serve as Bcl-xl protein inhibitors, which would consequently lead to apoptotic process in ovarian cancers.
Developing a broadly applicable pyrF-based genetic manipulation system in Acinetobacter baumannii

Acinetobacter baumannii is an emergency pathogenic bacterium for its multidrug-resistance and high mortality rates after infection. In-depth genetic analysis of A. baumannii virulence and drug-resistant genes is highly desirable. Existing methods for genetic manipulation of A. baumannii mainly rely on the use of antibiotic as the selectable marker, and the sacB/sucrose as the counter-selectable marker, which is inconvenient and inappropriate for all research of A. baumannii. Based on the highly conserved pyrF gene and its conserved 500bp-flanking sequence, we quickly and easily generated the pyrF-deleted mutants as the uracil auxotrophic host strain in three model strains and 11 clinical strains. The pyrF-carried vectors constructed for gene editing with pyrF/5-FOA as the counter-selection were conveniently and time-saving in these pyrF-deleted mutants. Utilizing the pyrF-based genetic manipulation system, we easily and efficiently modified the cas gene and CRISPR sequence of I-F CRISPR-Cas system in A. baumannii AYE, and detected the CRISPR interference and adaptation in these mutants. In summary, the pyrF-based genetic manipulation system could be broadly applicable used for efficiently maker-less gene editing in most A. baumannii strains.
Catalysis in electrochemistry : from fundamental to strategies for fuel cell development

Preface ix Preface to the Wiley Series on Electrocatalysis and Electrochemistry xi Contributors xiii 1. Volcano Curves in Electrochemistry 1 Roger Parsons 2. Electrocatalysis: A Survey of Fundamental Concepts 17 Alejandro Jorge Arvia, Agustin Eduardo Bolzan, and Miguel Angel Pasquale 3. Dynamics and Stability of Surface Structures 67 Margret Giesen and Guillermo Beltramo 4. Electrocatalytic Properties of Stepped Surfaces 127 Juan M. Feliu, Enrique Herrero, and Victor Climent 5. Computational Chemistry Applied to Reactions in Electrocatalysis 165 Axel Gross and Sebastian Schnur 6. Catalysis of Electron Transfer at Metal Electrodes 197 Elizabeth Santos and Wolfgang Schmickler 7. Combining Vibrational Spectroscopy and Density Functional Theory for Probing Electrosorption and Electrocatalytic Reactions 223 Marc T. M. Koper 8. Electrochemical Catalysts: From Electrocatalysis to Bioelectrocatalysis 249 Alejandro Jorge Arvia, Agustin Eduardo Bolzan, and Miguel Angel Pasquale 9. Electrocatalysis at Bimetallic Surfaces Obtained by Surface Decoration 297 Helmut Baltruschat, Siegfried Ernst, and Nicky Bogolowski 10. CO Adsorption on Platinum Electrodes 339 Angel Cuesta and Claudio Gutierrez 11. Exploring Metal Oxides: A Theoretical Approach 375 Monica Calatayud and Frederik Tielens 12. Electrocatalysis at Liquid Liquid Interfaces 427 Bin Su, Hubert H. Girault, and Zdenek Samec 13. Platinum-Based Supported Nanocatalysts for Oxidation of Methanol and Ethanol 453 Ernesto R. Gonzalez, Edson A. Ticianelli, and Ermete Antolini 14. Impact of Electrochemical Science on Energy Problems 487 Elizabeth Santos and Wolfgang Schmickler Index 499
A scalar Poincaré map for struggling in Xenopus tadpoles

Synaptic plasticity is widely found in many areas of the central nervous system. In particular, it is believed that synaptic depression can act as a mechanism to allow simple networks to generate a range of different firing patterns. The simplicity of the locomotor circuit in hatchling Xenopus tadpoles provides an excellent place to understand such basic neuronal mechanisms. Depending on the nature of the external stimulus, tadpoles can generate two types of behaviours: swimming when touched and slower, stronger struggling movements when held. Struggling is associated with rhythmic bends of the body and is accompanied by anti-phase bursts in neurons on each side of the spinal cord. Bursting in struggling is thought to be governed by a short-term synaptic depression of inhibition. To better understand burst generation in struggling, we study a minimal network of two neurons coupled through depressing inhibitory synapses. Depending on the strength of the synaptic conductance between the two neurons, such a network can produce symmetric n – n anti-phase bursts, where neurons fire n spikes in alternation, with the period of such solutions increasing with the strength of the synaptic conductance. Using a fast/slow analysis, we reduce the multidimensional network equations to a scalar Poincaré burst map. This map tracks the state of synaptic depression from one burst to the next, and captures the complex bursting dynamics of the network. Fixed points of this map are associated with stable burst solutions of the full network model, and are created through fold bifurcations of maps. We prove that the map has an infinite number of stable fixed points for a finite coupling strength interval, suggesting that the full two-cell network also can produce n – n bursts for arbitrarily large n. Our findings further support the hypothesis that synaptic depression can enrich the variety of activity patterns a neuronal network generates.
Prediction of Alzheimer's disease using multi-variants from a Chinese genome-wide association study

Abstract Previous genome-wide association studies have identified dozens of susceptibility loci for sporadic Alzheimer’s disease, but few of these loci have been validated in longitudinal cohorts. Establishing predictive models of Alzheimer’s disease based on these novel variants is clinically important for verifying whether they have pathological functions and provide a useful tool for screening of disease risk. In the current study, we performed a two-stage genome-wide association study of 3913 patients with Alzheimer’s disease and 7593 controls and identified four novel variants (rs3777215, rs6859823, rs234434, and rs2255835; Pcombined = 3.07 × 10−19, 2.49 × 10−23, 1.35 × 10−67, and 4.81 × 10−9, respectively) as well as nine variants in the apolipoprotein E region with genome-wide significance (P < 5.0 × 10−8). Literature mining suggested that these novel single nucleotide polymorphisms are related to amyloid precursor protein transport and metabolism, antioxidation, and neurogenesis. Based on their possible roles in the development of Alzheimer’s disease, we used different combinations of these variants and the apolipoprotein E status and successively built 11 predictive models. The predictive models include relatively few single nucleotide polymorphisms useful for clinical practice, in which the maximum number was 13 and the minimum was only four. These predictive models were all significant and their peak of area under the curve reached 0.73 both in the first and second stages. Finally, these models were validated using a separate longitudinal cohort of 5474 individuals. The results showed that individuals carrying risk variants included in the models had a shorter latency and higher incidence of Alzheimer’s disease, suggesting that our models can predict Alzheimer’s disease onset in a population with genetic susceptibility. The effectiveness of the models for predicting Alzheimer’s disease onset confirmed the contributions of these identified variants to disease pathogenesis. In conclusion, this is the first study to validate genome-wide association study-based predictive models for evaluating the risk of Alzheimer’s disease onset in a large Chinese population. The clinical application of these models will be beneficial for individuals harbouring these risk variants, and particularly for young individuals seeking genetic consultation.
Impact of exploitative learning strategy on Malaysian SMEs' creativity and innovation capabilities

Small and medium-sized enterprises (SMEs) can be considered as learning enterprises due to their competitive natures. The aim of the present study is to examine the notion of exploitative learning strategy, which is practised among Malaysian SMEs to determine to which extent it will result in creativity and innovation. A questionnaire was developed and was distributed among 1,850 SMEs online from which 206 surveys were thoroughly completed and returned. A variance-based structural equation modelling technique (VB-SEM) was utilised to assess the measurement as well as the structural relationships for exogenous and endogenous constructs. Results of hypothesis testing indicate that the exploitative learning strategy has a significant, positive role in improvisational creativity, compositional creativity and innovation while its indirect effect on innovation capability is also significant through compositional creativity. This study also finds that the number of employees moderates the relationship between exploitative learning strategy, improvisational creativity and innovation in SMEs.