Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of CETP as a molecular target for estrogen positive breast cancer cell death by cholesterol depleting agents

Cholesterol and its metabolites act as steroid hormone precursors, which promote estrogen receptor positive (ER+) breast cancer (BC) progression. Development of cholesterol targeting anticancer drugs has been hindered due to the lack of knowledge of viable molecular targets. Till now, Cholesteryl ester transfer protein (CETP) has been envisaged as a feasible molecular target in atherosclerosis, but for the first time, we show that CETP contributes to BC cell survival when challenged with cholesterol depleting agents. We show that MCF-7 CETP knockout BC cells pose less resistance towards cytotoxic compounds (Tamoxifen and Acetyl Plumbagin (AP)), and were more susceptible to intrinsic apoptosis. Analysis of differentially expressed genes using Ingenuity Pathway Analysis (IPA), in vivo tumor inhibition, and in vitro phenotypic responses to AP revealed a unique CETP-centric cholesterol pathway involved in sensitizing ER+ BC cells to intrinsic mitochondrial apoptosis. Furthermore, analysis of cell line, tissue and patient data available in publicly available databases linked elevated CETP expression to cancer, cancer relapse and overall poor survival. Overall, our findings highlight CETP as a pharmacologically relevant and unexploited cellular target in BC. The work also highlights AP as a promising chemical entity for preclinical investigations as a cholesterol depleting anticancer therapeutic agent.
Eyeblink conditioning in 12-day-old rats using pontine stimulation as the conditioned stimulus

A fundamental issue in developmental science is whether ontogenetic changes in memory are caused by the development of cellular plasticity mechanisms within the brain's memory systems or maturation of sensory inputs to the memory systems. Here, we provide evidence that the development of eyeblink conditioning, a form of associative learning that depends on the cerebellum, is driven by the development of sensory inputs rather than the development of neuronal plasticity mechanisms. We find that rats as young as 12 days old show associative eyeblink conditioning when pontine stimulation is used in place of an external (e.g., a tone) conditioned stimulus. Eyeblink-conditioned responses established with pontine stimulation in 12-day-old rats were reversibly abolished by an infusion of muscimol into the cerebellar interpositus nucleus. The findings suggest that cerebellar neurons are capable of supporting associative learning-specific plasticity in vivo in very immature animals if given sufficient afferent stimulation.
learning colour words is slow: a cross-situational learning account

research into child language reveals that it takes a long time for children to learn the correct mapping of colour words. steels & belpaeme's (s&b's) guessing game, however, models fast learning of words. we discuss computational studies based on cross-situational learning, which yield results that are more consistent with the empirical child language data than those obtained by s&b.
Comparison of Step Length Estimators from Weareable Accelerometer Devices

Wearable accelerometry provides easily portable systems that supply real-time data adequate for gait analysis. When they do not provide direct measurement of a spatio-temporal parameter of interest, such as step length, it has to be estimated with a mathematical model from indirect sensor measurements. In this work we are concerned with the accelerometry-based estimation of the step length in straight line human walking. We compare five step length estimators. Measurements were taken from a group of four adult men, adding up a total of 800 m per individual of walking data. Also modifications to these estimators are proposed, based on biomechanical considerations. Results show that this modifications lead to improvements of interest over previous methods
Ceramide synthase inhibitor fumonisin B1 inhibits apoptotic cell death in SCC17B human head and neck squamous carcinoma cells after Pc4 photosensitization

The sphingolipid ceramide modulates stress-induced cell death and apoptosis. We have shown that ceramide generated via de novo sphingolipid biosynthesis is required to initiate apoptosis after photo-dynamic therapy (PDT). The objective of this study was to define the role of ceramide synthase (CERS) in PDT-induced cell death and apoptosis using fumonisin B1 (FB), a CERS inhibitor. We used the silicon phthalocyanine Pc4 for PDT, and SCC17B cells, as a clinically-relevant model of human head and neck squamous carcinoma. zVAD-fmk, a pan-caspase inhibitor, as well as FB, protected cells from death after PDT. In contrast, ABT199, an inhibitor of the anti-apoptotic protein Bcl2, enhanced cell killing after PDT PDT-induced accumulation of ceramide in the endoplasmic reticulum and mitochondria was inhibited by FB. PDT-induced Bax translocation to the mitochondria and cytochrome c release were also inhibited by FB. These novel data suggest that PDT-induced cell death via apoptosis is CERS/ceramide-dependent.
Azithromycin Causes a Novel Proarrhythmic Syndrome

Background— The widely used macrolide antibiotic azithromycin increases risk of cardiovascular and sudden cardiac death, although the underlying mechanisms are unclear. Case reports, including the one we document here, demonstrate that azithromycin can cause rapid, polymorphic ventricular tachycardia in the absence of QT prolongation, indicating a novel proarrhythmic syndrome. We investigated the electrophysiological effects of azithromycin in vivo and in vitro using mice, cardiomyocytes, and human ion channels heterologously expressed in human embryonic kidney (HEK 293) and Chinese hamster ovary (CHO) cells. Methods and Results— In conscious telemetered mice, acute intraperitoneal and oral administration of azithromycin caused effects consistent with multi-ion channel block, with significant sinus slowing and increased PR, QRS, QT, and QTc intervals, as seen with azithromycin overdose. Similarly, in HL-1 cardiomyocytes, the drug slowed sinus automaticity, reduced phase 0 upstroke slope, and prolonged action potential duration. Acute exposure to azithromycin reduced peak SCN5A currents in HEK cells (IC50=110±3 &mgr;mol/L) and Na+ current in mouse ventricular myocytes. However, with chronic (24 hour) exposure, azithromycin caused a ≈2-fold increase in both peak and late SCN5A currents, with findings confirmed for INa in cardiomyocytes. Mild block occurred for K+ currents representing IKr (CHO cells expressing hERG; IC50=219±21 &mgr;mol/L) and IKs (CHO cells expressing KCNQ1+KCNE1; IC50=184±12 &mgr;mol/L), whereas azithromycin suppressed L-type Ca++ currents (rabbit ventricular myocytes, IC50=66.5±4 &mgr;mol/L) and IK1 (HEK cells expressing Kir2.1, IC50=44±3 &mgr;mol/L). Conclusions— Chronic exposure to azithromycin increases cardiac Na+ current to promote intracellular Na+ loading, providing a potential mechanistic basis for the novel form of proarrhythmia seen with this macrolide antibiotic.
Variations in physician practice: the role of uncertainty.

Prologue: Nothing more underscores the reality that medical care represents a melding of art and science than the wide variation in the use and cost of that care. One of the factors that leads to practice variations is uncertainty in the minds of doctors about how to approach a particular medical problem. David Eddy, who holds a medical degree from the University of Virginia and a doctor of philosophy degree in applied mathematics from Stanford University, has made a professional career of reducing uncertainty in medical practice and helping doctors find their way to the most efficacious treatments for patients. Eddy operates at the intersection of math and medicine, applying probability theory to the uncertainty of approaches to care. Although his pursuits have not always been appreciated by the profession —many of his conclusions cut against the grain of conventional medical judgment—Eddy has been awarded the Manchester Prize by the Operations Research Society of America, the most prestigious honor that.
Application of the BacT/ALERTR 3D system for sterility testing of injectable products

Sterility testing as described in the pharmacopoeia compendia requires a 14-day incubation period to obtain an analytical result. Alternative methods that could be applied to evaluating product sterility are especially interesting due to the possibility of reducing this incubation period and thus the associated costs. The aims of this study were to evaluate the performance of the BacT/ALERTR 3D system in detecting microorganisms in large-volume parenteral solutions that were intentionally contaminated and to compare this system to pharmacopoeia sterility testing using the membrane filtration method. The results indicated that there were no significant differences between the methods regarding the ability to detect microbial contamination; however, detection with the BacT/ALERTR 3D system was faster compared to the pharmacopoeia method. Therefore, the BacT/ALERTR 3D system is a viable alternative for assessing the sterility of injectable products.
DNA-metabarcoding uncovers the diversity of soil-inhabiting fungi in the tropical island of Puerto Rico

Soil fungal communities in tropical regions remain poorly understood. In order to increase the knowledge of diversity of soil-inhabiting fungi, we extracted total DNA from top-organic soil collected in seven localities dominated by four major ecosystems in the tropical island of Puerto Rico. In order to comprehensively characterize the fungal community, we PCR-amplified the internal transcribed spacer 2 (ITS2) fungal barcode using newly designed degenerated primers and varying annealing temperatures to minimize primer bias. Sequencing results, obtained using Ion Torrent technology, comprised a total of 566,613 sequences after quality filtering. These sequences were clustered into 4,140 molecular operational taxonomic units (MOTUs) after removing low frequency sequences and rarefaction to account for differences in read depth between samples. Our results demonstrate that soil fungal communities in Puerto Rico are structured by ecosystem. Ascomycota, followed by Basidiomycota, dominates the diversity of fungi in soil. Amongst Ascomycota, the recently described soil-inhabiting class Archaeorhizomycetes was present in all localities, and taxa in Archaeorhizomycetes were among the most commonly observed MOTUs. The Basidiomycota community was dominated by soil decomposers and ectomycorrhizal fungi with a distribution strongly affected by local variation to a greater degree than Ascomycota.
Distinguishing topical and social groups based on common identity and bond theory

Social groups play a crucial role in social media platforms because they form the basis for user participation and engagement. Groups are created explicitly by members of the community, but also form organically as members interact. Due to their importance, they have been studied widely (e.g., community detection, evolution, activity, etc.). One of the key questions for understanding how such groups evolve is whether there are different types of groups and how they differ. In Sociology, theories have been proposed to help explain how such groups form. In particular, the common identity and common bond theory states that people join groups based on identity (i.e., interest in the topics discussed) or bond attachment (i.e., social relationships). The theory has been applied qualitatively to small groups to classify them as either topical or social. We use the identity and bond theory to define a set of features to classify groups into those two categories. Using a dataset from Flickr, we extract user-defined groups and automatically-detected groups, obtained from a community detection algorithm. We discuss the process of manual labeling of groups into social or topical and present results of predicting the group label based on the defined features. We directly validate the predictions of the theory showing that the metrics are able to forecast the group type with high accuracy. In addition, we present a comparison between declared and detected groups along topicality and sociality dimensions.
Neonatal Mortality and Prevalence of Practices for Newborn Care in a Squatter Settlement of Karachi, Pakistan: A Cross-Sectional Study

Background During the past two decades there has been a sustained decline in child and infant mortality, however neonatal mortality has remained relatively unchanged. Almost all neonatal deaths (99%) occur in developing countries, where the majority are delivered at homes. Evidence suggests that these deaths could be prevented by simple, inexpensive practices and interventions during the pregnancy, delivery and postnatal period. In Pakistan over the last decade extensive efforts have been made by the international donors and government to implement these practices. However, limited attempts have been made to explore if these efforts have made a difference at the grass root level. This study assessed the burden of neonatal mortality and prevalence of practices for newborn care in a squatter settlement of Karachi, Pakistan. Methodology/Principal Findings A community based cross-sectional study was performed. A pre-tested structured questionnaire was administered to 565 women who had recently delivered. Information was collected on neonatal morbidity, mortality and practices of women regarding care during pregnancy, child birth and for newborn, till 28th day of birth. Although 70% of women mentioned receiving antenatal care by a skilled provider, only 54.5% had four or more visits. Tetanus toxoid was received by 79% of women while only 56% delivered at a health care facility by a skilled attendant. Newborn care practices like bathing the baby immediately after birth (56%), giving pre-lacteals (79.5%), late initiation of breast feeding (80.3%), application of substances on umbilical cord (58%) and body massage (89%) were common. Most neonates (81.1%) received BCG injection and polio drops after birth. Neonatal mortality rate was 27/1000 live births with the majority of deaths occurring during the first three days of life. Conclusion Even after years of efforts by government and nongovernmental sector to reduce newborn morbidity and mortality, inadequate antenatal care, home deliveries and unhealthy newborn care practices are highly prevalent. This leads us to important questions of why practices and behaviors have not changed. Who is responsible and what strategies are needed to bring this change?
Natural selection for the Duffy-null allele in the recently admixed people of Madagascar

While gene flow between distantly related populations is increasingly recognized as a potentially important source of adaptive genetic variation for humans, fully characterized examples are rare. In addition, the role that natural selection for resistance to vivax malaria may have played in the extreme distribution of the protective Duffy-null allele, which is nearly completely fixed in mainland sub-Saharan Africa and absent elsewhere, is controversial. We address both these issues by investigating the evolution of the Duffy-null allele in the Malagasy, a recently admixed population with major ancestry components from both East Asia and mainland sub-Saharan Africa. We used genome-wide genetic data and extensive computer simulations to show that the high frequency of the Duffy-null allele in Madagascar can only be explained in the absence of positive natural selection under extreme demographic scenarios involving high genetic drift. However, the observed genomic single nucleotide polymorphism diversity in the Malagasy is incompatible with such extreme demographic scenarios, indicating that positive selection for the Duffy-null allele best explains the high frequency of the allele in Madagascar. We estimate the selection coefficient to be 0.066. Because vivax malaria is endemic to Madagascar, this result supports the hypothesis that malaria resistance drove fixation of the Duffy-null allele in mainland sub-Saharan Africa.
Annular Oligomeric Amyloid Intermediates Observed by in Situ Atomic Force Microscopy*

Amyloidoses and related protein deposition diseases involve the transformation of normally soluble proteins into insoluble deposits, usually fibrillar in nature. Although it was originally assumed that the fibrils were the toxic species, this assumption has recently been called into question. Accumulating evidence in several systems suggests that oligomeric intermediates on the aggregation pathway may be toxic. In the present study we used in situ atomic force microscopy to monitor aggregation in aqueous solution in real time. The sample used was an amyloidogenic immunoglobulin light chain, involved in AL or light chain amyloidosis. The nature of the observed oligomeric intermediates was dependent on the conditions of incubation, especially pH and ionic strength. Several different aggregation intermediates with a variety of morphologies, including annular or torus-shaped species, were observed. The data indicate that protein aggregation can be very complex, involving a variety of different oligomeric intermediates whose population will be determined by the kinetic and thermodynamic competition between them.
Polyurethane-based scaffolds for myocardial tissue engineering

Bi-layered scaffolds with a 0°/90° lay-down pattern were prepared by melt-extrusion additive manufacturing (AM) using a poly(ester urethane) (PU) synthesized from poly(ε-caprolactone) diol, 1,4-butandiisocyanate and l-lysine ethyl ester dihydrochloride chain extender. Rheological analysis and differential scanning calorimetry of the starting material showed that compression moulded PU films were in the molten state at a higher temperature than 155°C. The AM processing temperature was set at 155°C after verifying the absence of PU thermal degradation phenomena by isothermal thermogravimetry analysis and rheological characterization performed at 165°C. Scaffolds highly reproduced computer-aided design geometry and showed an elastomeric-like behaviour which is promising for applications in myocardial regeneration. PU scaffolds supported the adhesion and spreading of human cardiac progenitor cells (CPCs), whereas they did not stimulate CPC proliferation after 1–14 days culture time. In the future, scaffold surface functionalization with bioactive peptides/proteins will be performed to specifically guide CPC behaviour.
Using Molecular Data to Detect Selection: Signatures from Recent Single Events

Different types and phases of a selective sweep (hard, soft, partial, polygenic) generate different patterns of departures from neutrality, and hence require different tests. It is thus not surprising that a large number of tests have been proposed that use sequence information to detect ongoing, or very-recently completed, episodes of selection. This chapter critically reviews over 50 such tests, which use information on allele-frequency change, linkage disequilibrium patterns, spatial allele-frequency patterns, site-frequency spectrum data, allele-frequency spectrum data, and haplotype structure. This chapter discusses the domain of applicability for each test, and their strengths and weaknesses. Finally, this chapter examines application of these methods in the search for recent, or ongoing, selection in humans and for genes involved in the domestication process in plants and animals.
Big Data Research in Information Systems: Toward an Inclusive Research Agenda

: Big data has received considerable attention from the information systems (IS) discipline over the past few years, with several recent commentaries, editorials, and special issue introductions on the topic appearing in leading IS outlets. These papers present varying perspectives on promising big data research topics and highlight some of the challenges that big data poses. In this editorial, we synthesize and contribute further to this discourse. We offer a first step toward an inclusive big data research agenda for IS by focusing on the interplay between big data’s characteristics, the information value chain encompassing people-process-technology, and the three dominant IS research traditions (behavioral, design, and economics of IS). We view big data as a disruption to the value chain that has widespread impacts, which include but are not limited to changing the way academics conduct scholarly work. Importantly, we critically discuss the opportunities and challenges for behavioral, design science, and economics of IS research and the emerging implications for theory and methodology arising due to big data’s disruptive effects.
Mast cells are necessary for the hypothermic response to LPS-induced sepsis.

As central nervous system residents, mast cells contain many cytokines and are localized primarily near large blood vessels in the diencephalon and within the leptomeninges, making them candidates for immune to neural "cross talk. " Using mast cell-deficient Kit(W-sh/W-sh) mice, we assessed the role of these cells in the thermoregulatory component of the immune response to lipopolysaccharide (LPS). Kit(W-sh/W-sh) and wild-type (WT) mice differed in several respects in response to injection of a high dose of LPS (1 mg/kg ip). Core temperature (T(c)) of WT mice decreased by approximately 3 degrees C, whereas Kit(W-sh/W-sh) mice did not become hypothermic but instead exhibited pronounced low-frequency T(c) oscillations around their baseline temperature. In addition, Kit(W-sh/W-sh) mice had lower levels of whole brain TNF-alpha but no differences in IL-1beta, IL-6, IFN-gamma, or histamine compared with WT mice following injection of the high dose of LPS, consistent with the role of TNF-alpha in sepsis. Kit(W-sh/W-sh) mice had increased resistance to LPS, and some survived a dose of LPS that was lethal in littermate controls. In contrast, Kit(W-sh/W-sh) and WT mice were similar in other aspects, namely, in the hyperthermia following injection of TNF-alpha (1.5 microg icv), reduced nighttime T(c) and locomotor activity (to 1 mg/kg LPS), response to a low dose of LPS (10 microg/kg ip), and response to subcutaneous turpentine injection. These results indicate that mast cells play a role in the regulation of thermoregulatory responses and survival following sepsis induction and suggest a brain site of action.
Brazilian Journal of Chemical Engineering OPTIMIZATION OF PRODUCTION OF 5-HYDROXYMETHYLFURFURAL FROM GLUCOSE IN A WATER : ACETONE BIPHASIC SYSTEM

5-Hydroxymethylfurfural (HMF) is considered to be an important building block for biorefineries and has a high potential for the production of chemicals and fuels. Production of HMF from glucose was studied using phosphoric acid as catalyst, in a water:acetone system with volume ratio of 1:2 and NaCl. An experimental design was applied to examine the influence of temperature, time and concentration of catalyst on the HMF yield. HMF yields of more than 50 % were obtained when using 200 °C, 8.4 min and 0.8% of catalyst. The temperature is the main factor influencing the HMF yield.