cssi/SciSciGPT-SciSciNet huggingface dataset:
Metabolic Dependencies in RAS-Driven Cancers

The ability to inhibit the RAS oncogene has been the holy grail of oncology because of the critical role of this gene in a multitude of tumor types. In addition, RAS-mutant tumors are among the most aggressive and refractory to treatment. Although directly targeting the RAS oncogene has proven challenging, an alternative approach for treating RAS-driven cancers is to inhibit critical downstream events that are required for tumor maintenance. Indeed, much focus has been put on inhibiting signaling cascades downstream of RAS. Recent studies have shown that oncogenic RAS promotes a metabolic reprogramming of tumor cells, shifting them toward an anabolic metabolism necessary to produce biomass to support unconstrained proliferation. These cancers also use a diverse set of fuel sources to meet their metabolic needs and have even developed a variety of mechanisms to act as metabolic scavengers to obtain necessary metabolic substrates from both extracellular and intracellular sources. Collectively, these adaptations can create "metabolic bottlenecks" whereby tumor cells rely on particular pathways or rate-limiting metabolites. In this regard, inhibiting individual or combinations of these metabolic pathways can attenuate growth in preclinical models. Because these dependencies are tumor selective and downstream of oncogenic RAS, there is the opportunity for therapeutic intervention. Although targeting tumor metabolism is still in the early days of translation to patients, our continued advances in understanding critical metabolic adaptations in RAS-driven cancers, as well as the ability to study this altered metabolism in relevant tumor models, will accelerate the development of new therapeutic approaches. Clin Cancer Res; 21(8); 1828-34. ©2015 AACR. See all articles in this CCR Focus section, "Targeting RAS-Driven Cancers."
Henry Steele Commager: Midcentury Liberalism and the History of the Present

Historian Henry Steele Commager (1902-98) was one of the leading American intellectuals of the mid-twentieth century. Author or editor of more than forty books, he taught for decades at New York University, Columbia University, and Amherst College and was a pioneer in the field of American studies. But Commager's work was by no means confined to the halls of the university: a popular essayist, lecturer, and political commentator, he earned a reputation as an activist for liberal causes and waged public campaigns against McCarthyism in the 1950s and the Vietnam War in the 1960s. In this book, Neil Jumonville uses Commager's career to explore a number of themes central to the intellectual history of postwar America. Examining the relationship between the midcentury generation of scholars and the baby boomer generation now in the university, he reassesses the legacy of the 1940s and 1950s and illuminates the background of the culture wars of today. He also offers a reevaluation of the ideas in the liberalism of the period, including a common American identity and shared culture, pragmatism, compromise, freedom of speech, and the benefits of at least a modest consensus on goals - ideas that in recent years have taken quite a beating in the public arena.
INSULIN-LOWERING MEDICATIONS IN POLYCYSTIC OVARY SYNDROME

Polycystic ovary syndrome (PCOS) is one of the most common reproductive abnormalities, affecting 5% of the population of reproductive-aged women. Its clinical manifestations include menstrual dysfunction and hyperandrogenic symptoms, and it can be associated with infertility, obesity, and metabolic dysfunction. A significant proportion of obese women with PCOS have insulin resistance greater than would be expected from their obesity alone, and some lean patients with PCOS are also more insulin resistant than expected. This insulin resistance is accompanied by a defect in insulin secretion, and recent studies have documented a dramatically increased rate of diabetes mellitus and impaired glucose tolerance in this subpopulation of young women. Medications that reduce serum insulin levels have been administered to women with PCOS to study the role of hyperinsulinemia in the pathophysiology of PCOS and to treat the condition. This article presents the evidence for hyperinsulinemia and insulin resistance in women and reviews the therapeutic response to insulin-lowering agents. Recommendations are made for further research and the use of these new agents in the treatment of PCOS.
Meta-analysis for pathway enrichment analysis when combining multiple genomic studies

Motivation: Many pathway analysis (or gene set enrichment analysis) methods have been developed to identify enriched pathways under different biological states within a genomic study. As more and more microarray datasets accumulate, meta-analysis methods have also been developed to integrate information among multiple studies. Currently, most meta-analysis methods for combining genomic studies focus on biomarker detection and meta-analysis for pathway analysis has not been systematically pursued. Results: We investigated two approaches of meta-analysis for pathway enrichment (MAPE) by combining statistical significance across studies at the gene level (MAPE_G) or at the pathway level (MAPE_P). Simulation results showed increased statistical power of meta-analysis approaches compared to a single study analysis and showed complementary advantages of MAPE_G and MAPE_P under different scenarios. We also developed an integrated method (MAPE_I) that incorporates advantages of both approaches. Comprehensive simulations and applications to real data on drug response of breast cancer cell lines and lung cancer tissues were evaluated to compare the performance of three MAPE variations. MAPE_P has the advantage of not requiring gene matching across studies. When MAPE_G and MAPE_P show complementary advantages, the hybrid version of MAPE_I is generally recommended. Availability: http://www.biostat.pitt.edu/bioinfo/ Contact: ctseng@pitt.edu Supplementary information:Supplementary data are available at Bioinformatics online.
Ruptured aortic aneurysm masquerading as phlegmasia cerulea.

Phlegmasia cerulea dolens, characterized by the triad of limb swelling, cyanosis, and acute ischemic pain, usually arises because of acute massive thrombosis of major deep, collateral, and superficial veins of an extremity. We report a patient with an atypically presenting ruptured aortic aneurysm masquerading as phlegmasia cerulea dolens. A 68-year-old man with a history of hypertension, intermittent claudication, and smoking presented with asthenia, macrohematuria, and mild back pain, as well as edema and blue mottling of the lower limbs and abdomen for 24 hours. The abdomen was nontender without a pulsatile mass or murmur. Computed tomography showed an 85-mm abdominal aortic aneurysm ruptured into the inferior vena cava. Phlegmasia cerulea dolens-like symptoms were explained by compromised venous outflow from the lower limbs because of an aortocaval fistula. The patient died of uncontrollable hemorrhage during emergent surgical repair. Three percent to 6% of patients with abdominal aortic aneurysm rupture present an aortocaval fistula, which can be suspected by the triad of abdominal or lower back pain, pulsatile abdominal mass, and machinery-type abdominal murmur. Left untreated, this condition rapidly leads to death from congestive heart failure. Only one third of patients are diagnosed before surgery because a fistula is often not suspected until unexplained massive hemorrhage occurs during the operation. Operative mortality is extremely high (34%). We propose that the clinical syndrome presented by our patient, a "blue fistula" frequently associated with aortocaval fistulae, be called phlegmasia cerulea non dolens, by analogy to Gregoire's "blue phlebitis."
Receptive Fields in Human Visual Cortex Mapped with Surface Electrodes

Most of our understanding of the functional organization of human visual cortex comes from lesion and functional imaging studies and by extrapolation from results obtained by neuroanatomical and neurophysiological studies in nonhuman primates. Although some single-unit and field potential recordings have been made in human visual cortex, none has provided quantitative characterization of spatial receptive fields (RFs) of individual sites. Here we use subdural electrodes implanted for clinical purposes to quantitatively measure response properties in different regions of human visual cortex. We find significant differences in RF size, response latency, and response magnitude for sites in early visual areas, versus sites in later stages of both the dorsal and ventral streams. In addition, we use this technique to estimate the cortical magnification factor in early human visual cortex. The spatial and temporal resolution of cortical surface recordings suggest that this technique is well suited to examine further issues in visual processing in humans.
Loss of transforming growth factor β signalling in the intestine contributes to tissue injury in inflammatory bowel disease

Background—Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract caused by an abnormal and uncontrolled immune response to one or more normally occurring gut constituents. Aim—Given the eVects of transforming growth factor ‚1 (TGF-‚1) on both the immune system and extracellular matrix, we postulated that alterations in TGF-‚ signalling in intestinal epithelial cells may play an important role in the development of IBD. Methods—TGF-‚ signalling was inactivated in mouse intestine by expressing a dominant negative mutant form of the TGF-‚ type II receptor under the control of the mouse intestinal trefoil peptide (ITF)/TFF3 promoter. Transgenic mice (ITF-dnRII) developed spontaneous colitis presenting with diarrhoea, haematochezia, and anal prolapse when not maintained under specific pathogen free (SPF) conditions. Under SPF conditions we induced colitis by mixing dextran sodium sulphate (DSS) in drinking water to examine the significance of loss of TGF-‚ signalling in the pathogenesis of IBD. Results—Transgenic mice showed increased susceptibility to DSS induced IBD, and elicited increased expression of major histocompatibility complex class II, generation of autoantibodies against intestinal goblet cells, and increased activity of matrix metalloproteinase in intestinal epithelial cells compared with wild-type littermates challenged with DSS. Conclusions—Deficiency of TGF-‚ signalling specifically in the intestine contributes to the development of IBD. Maintenance of TGF-‚ signalling may be important in regulating immune homeostasis in the intestine (Gut 2001;49:190‐198)
Design, synthesis, and biological evaluation of a scaffold for iGluR ligands based on the structure of (-)-kaitocephalin.

The design and synthesis of four 2,2-disubstituted dihydrobenzofurans that are structurally related to several glutamate-containing natural products, including (-)-dysiherbaine, is described. Biological evaluation of these analogs shows that one is a KA receptor antagonist and another is an NMDA receptor agonist.
Effects of temperature, sex, and genetic background on coloration of Choristoneura spp. (Lepidoptera: Tortricidae) populations in South-Central Oregon

Coloration of larval, pupal, and adult progeny of Choristoneura spp. collected from Pseudotsuga menziesii (Mirb.) Franco and Abies concolor (Gord. & Glend.) Lindl. in south-central Oregon depended on the temperature at which the insects were reared. Sex and genetic background were also major sources of variation in coloration. Many of the characters which varied with temperature were thought to be of value in distinguishing C. occidentalis Freeman from C. retiniana (Walsingham). The association between a combination of larval characters and a combination of adult forewing maculations, though weak, allows a calculation of the probability that an adult belongs to a certain lineage defined by larval features. Individuals from mixed families were particularly difficult to categorize because of the variation encountered and the sensitivity of their appearance to rearing temperature. The biological significance of this variation and its implications to pest management are discussed.
Performance evaluation of transaction processing coupling architectures for handling system dynamics

As the demand for high volume transaction processing grows, coupling multiple computing nodes becomes increasingly attractive. This paper presents a comparison on the resilience of the performance to system dynamics of three architectures for transaction processing. In the shared nothing (SN) architecture, neither disks nor memory is shared. In the shared disk (SD) architecture, all disks are accessible to all nodes while in the shared intermediate memory (SIM) architecture, a shared intermediate level of memory is introduced. A transaction processing system needs to be configured with enough capacity to cope with the dynamic variation of load or with a node failure. Three specific scenarios are considered: 1) a sudden surge in load of one transaction class, 2) varying transaction rates for all transaction classes, and 3) failure of a single processing node. We find that the different architectures require different amounts of capacity to be reserved to cope with these dynamic situations. We further show that the data sharing architecture, especially in the case with shared intermediate memory, is more resilient to system dynamics and requires far less contingency capacity compared to the SN architecture. >
Seasonal Variation of Coastal Resort Visitors: Hilton Head Island

This study identified numerous significant differences in visitors to Hilton Head Island according to season. The most useful are length of stay according to accommodation type, attributes important in the decision to visit, and trip origin. The study suggests that approaching segmentation by seasonality is a useful practice.
The Multi-Hex Prototype Experiment

The authors describe the Multi-Hex Prototype Experiment (MHPE), which was developed to experimentally investigate the technologies associated with the active control of flexible structures. The MHPE has as its main component a structure that was designed to emulate the generic properties of large space structures, such as high-frequency RF or optical antennas and solar concentrators. The authors describe the primary features of the MHPE and present some experimental results which illustrate the efficacy of system identification and active control. Experimentation has provided validation of system identification using the eigensystem realization algorithm and has also shown the ability of active control to provide significant vibration attenuation. >
Optimization of Monotonic Linear Progressive Queries Based on Dynamic Materialized Views

There is an increasing demand to efficiently process emerging types of queries, such as progressive queries(PQs),fromcontemporarydatabaseapplicationsincludingtelematics,e-commerceandsocial media.Unlikeconventionalqueries,aPQconsistsofasetofstep-queries(SQ).Auserformulatesanew SQ on the fly based on the result(s) from the previous SQ(s). Existing database management systems were not designed to efficiently process such queries. In this paper, we present a novel technique to efficiently process a special type of PQ, called monotonic linear PQs, based on dynamically materializedviews.ThekeyideaistocreateasuperiorrelationshipgraphforSQsfromhistoricalPQs that can be used to estimate the benefit of keeping the current SQ result as a materialized view. The materialized views are used to improve the performance of future SQs. A new storage structure for the materialized views set is designed to facilitate efficient search for a usable view to answer a given SQ. Algorithms/strategies to efficiently construct a superior relationship graph, dynamically select materialized views, effectively manage the materialized views set and efficiently search for usable views are discussed. Experiment results demonstrate that our proposed technique is quite promising.
Advanced services for rural telephony

Subscriber demands in rural areas for enhanced features and services equivalent to those available in metro areas are increasing. These demands are driving intelligence and functionality currently associated with metropolitan digital switches down to the access network, a trend that will lead to an increasingly distributed switch architecture. This paper examines these requirements, and describes a method of interconnecting the DMS 10 rural digital switch to the DMS Super Node exchange in order to provide cost-effective access to the sophisticated features of the DMS Super Node host, as well as stand-alone implementation of specific sophisticated features directly in the DMS-10 using a Reduced Instruction Set Computing (RISC) processor.
Finding Protoevangelical Faith: A Summary of Four Ethnographic Studies

This article presents a summary of the findings from four ethnographic studies of postevangelical groups interpreting and applying the theology and praxis of Dr. Dallas Willard. Willard’s works have become increasingly attractive to emerging generations of so called “postevangelical” Christians protesting the perceived excesses and hegemony of mainstream evangelical religion in the United States. Willardian theology is seen as providing a positive alternative to contemporary versions of evangelicalism. For increasing numbers of disaffected evangelicals with postmodern sensibilities, Willard’s “protoevangelical” vision offers a more robust doctrine of God, a return to the primacy of discipleship to Christ, and the experience of a holistic and integrated life in the Kingdom of God.
Paclitaxel and recombinant human granulocyte colony-stimulating factor as initial chemotherapy for metastatic breast cancer.

PURPOSEA phase II study of Taxol (paclitaxel; Bristol-Myers Squibb Co, Princeton, NJ) as initial chemotherapy for metastatic breast cancer was conducted. Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was used to ameliorate myelosuppression, the anticipated dose-limiting toxicity.PATIENTS AND METHODSTwenty-eight patients with bidimensionally measurable breast cancer who had not received prior chemotherapy for metastatic disease were treated. Taxol was administered at 250 mg/m2 as a continuous 24-hour intravenous (i.v.) infusion every 21 days. rhG-CSF was administered at 5 micrograms/kg/d subcutaneously on days 3 through 10.RESULTSObjective responses were observed in 16 of 26 assessable patients (62%; 95% confidence interval, 41% to 80%). There were three (12%) complete responses (CRs) and 13 (50%) partial responses (PRs). Ten of 16 patients (63%) who had received prior adjuvant chemotherapy responded, which included one CR and four PRs among eight patients who had received prior doxorub...
Use of Serious Games to Teach Engineering Design Fundamentals

There is a strong need to infuse engineering content and design principles for student learning into diverse K-12 technology education(Gattie etal., 2007; Hailey et al., 2005).Over the past decade, almost $3 billion has been invested in educational technology. In 2012, more than $1 billion was raised for educational technology to improve student motivation and learning processes (Nordin, 2013). With the investment in technology and the need for new instructional techniques to improve student learning, we investigate new innovative instructional materials like serious games and check their effectiveness at the K-12 level to infuse interest in the students to pursue STEM majors. Engineering design is hard to learn and harder to teach.Engineering design skills cannot be adequately taught in lectures alone; a more active learning experience is required (Albers et al., 2009).Serious games can be used for education at all levels, from preschool and elementary school, through middle school and high school, into colleges and universities, and even into the job market. In this paper, we talk about the design, development and implementation of an engineering design serious game developed by Toolwire,a company with expertise in educational technologies in partnership with the Laboratory for Innovative Technology and Engineering Education (LITEE), a university center with extensive expertise in educational pedagogy and theories. The objective was to provide an active learning experience linking the engineering design process to a real-world simulation.A mixed methods approach (Creswell, 2013) was used to evaluate the effectiveness of the serious game. Analysis of the results showed that the students enjoyedworkingwith the serious game and this experience helped them in understanding the design process in a more effective manner.
Incipient fault diagnosis based on improved principal component analysis for power transformer

Based on the transformer DGA(Dissolved Gas Analysis),an improved PCA(Principal Component Analysis) is proposed to diagnose the incipient fault of transformer. Different from the traditional PCA,it standardizes the sample indices with the sum of their absolute values,which eliminates the numeric magnitude difference between indices while keeps their information differences. The principal components are selected according to the cumulative contribution rate and the Euclidean distances between them are clustered to determine the fault state of transformer. Diagnosis instances show that,the proposed method effectively improves the diagnosis accuracy of transformer incipient faults.
33 LINKAGE OF CHROMOSOME 1q25-43 REGION TO CLINICAL FEATURES OF SYSTEMIC LUPUS ERYTHEMATOSUS

Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of auto-antibodies and a diverse array of clinical manifestations. Genetic predisposition clearly plays a role in the risk for developing SLE. In recent years, genome scans have identified several SLE susceptibility loci, including the chromosome 1q25-43 region, which is syntenic with a susceptibility interval identified in murine SLE models. In this study, we looked for associations between the observed genetic linkage of the chromosome 1q regions to SLE with clinical manifestations of SLE. By grouping families on the basis of common associated traits, it is thought that the sample heterogeneity is decreased while increasing the power to detect SLE susceptibility genes. Methods We stratified a cohort of 125 multiplex families (60 Caucasian, 34 Asian, 19 Hispanic, 9 African, and 3 mixed) containing 152 SLE-affected sibpairs by the presence of a particular clinical feature of SLE in at least one family member, and compared the resulting linkage to SLE with the linkage signal derived from families lacking the clinical feature. Non-parametric multipoint linkage analysis was performed on 16 microsatellite markers spanning the 1q25-43 susceptibility region (75.46 cM) using GENEHUNTER, a program which allows complete multipoint analysis with a large number of highly polymorphic markers. Results The strongest evidence for linkage was detected for two SLE-related traits: neuropsychiatric symptoms and anti-double-stranded DNA (anti-dsDNA) autoantibodies. The highest non-parametric linkage (NPL) score of 2.45 (p = 0.007) at D1S491 (228 cM) in 1q32.2 was obtained in families with at least one SLE-affected member positive for anti-dsDNA. In the subset of families with neuropsychiatric symptoms (seizures and/or psychosis), a NPL score of 2.34 (p = 0.01) was observed at D1S235 (255 cM) in 1q42.3.
Functional Heterogeneity in the Lungs

The purpose of this symposium is to compare amongst several organs the functionally important forms of heterogeneity, their anatomical basis, how they compromize the ability of each organ to perform its duties, how heterogeneity can be measured, and how heterogeneity evolves from health to disease.
Interaction Between Light and Photosynthetic Microorganisms

Abstract This chapter aims to introduce the physical concepts and to provide the experimental and theoretical frameworks necessary to understand and to quantify the interaction between light and photosynthetic microorganisms. Indeed, light transfer is arguably the most critical aspect to consider in designing, optimizing, and operating photobioreactors of all sizes for the production of a wide range of value-added products. This chapter presents state-of-the art theoretical and experimental methods for determining the scattering phase function and the absorption and scattering cross-sections of unicellular and multicellular microorganisms as well as of colonies. An extensive database of these so-called radiation characteristics over the photosynthetically active radiation region is presented for a wide variety of promising freshwater and marine microalgae, cyanobacteria, and nonsulfur purple bacteria with various shapes, sizes, pigments, and responses to stresses. The effects of photoacclimation and of progressive and sudden nitrogen starvation on the radiation characteristics are illustrated with Nannochloropsis oculata . Finally, limitations of current approaches are discussed and future research directions are suggested.
Understanding Natural Language Queries over Relational Databases

Natural language has been the holy grail of query interface designers, but has generally been considered too hard to work with, except in limited specific circumstances. In this paper, we describe the architecture of an interactive natural language query interface for relational databases. Through a carefully limited interaction with the user, we are able to correctly interpret complex natural language queries, in a generic manner across a range of domains. By these means, a logically complex English language sentence is correctly translated into a SQL query, which may include aggregation, nesting, and various types of joins, among other things, and can be evaluated against an RDBMS.We have constructed a\ system, NaLIR (Natural Language Interface for Relational databases), embodying these ideas. Our experimental assessment, through user studies, demonstrates that NaLIR is good enough to be usable in practice: even naive users are able to specify quite complex ad-hoc queries.
Biochemical Analysis of Caspase-8-dependent Proteolysis of IRF3 in Virus-infected Cells

Interferon regulatory factor 3 (IRF3) is a transcription factor, which is critical for the antiviral response against a wide range of viruses (Hiscott, 2007; Ikushima et al., 2013). It gets activated in virus- infected cells via Toll like receptors (TLRs), RIG-I (retinoic acid inducible gene 1) like receptors (RLRs), cyclic GMP-AMP synthase (cGAS) – stimulator of interferon genes (STING), which are sensors of viral components in the cells (Chattopadhyay and Sen, 2014a; 2014b; Hiscott, 2007). IRF3 is a cytoplasmic protein, upon activation by virally activated sensors it gets phosphorylated, translocated to the nucleus and binds to the interferon-sensitive response element (ISRE) of the gene promoters to induce their transcription (Hiscott, 2007). IRF3 has other functions, including direct stimulation of apoptosis in virus- infected cells. In this pathway, the transcriptional activity of IRF3 is not required (Chattopadhyay et al., 2013b; Chattopadhyay et al., 2016; Chattopadhyay et al., 2010; Chattopadhyay and Sen, 2010; Chattopadhyay et al., 2011). These pathways are negatively regulated by host factors as well as by viruses. Our studies indicate that IRF3 can be proteolytically processed by caspase-8-dependent cleavage (Sears et al., 2011). A specific site in IRF3 is targeted by caspase-8, activated in RNA or DNA virus-infected and dsRNA-stimulated cells (Sears et al., 2011). The direct involvement of caspase-8 was confirmed by in vitro cleavage assay using recombinant proteins and in vivo by virus activated caspase- 8. The proteolytic cleavage of IRF3 can be inhibited by chemical inhibition or genetic ablation of caspase-8. The cleavage of IRF3 removes the activated pool of IRF3 and thus can be used as a pro- viral mechanism (Figure 1). Using a C-terminally epitope-tagged human IRF3, we analyzed the cleavage of IRF3 in virus-infected cells. Moreover, we used recombinant proteins in vitro to conclude that IRF3 is a substrate of caspase-8 (Sears et al., 2011). In the current protocol, we have outlined a simple and detailed procedure to biochemically analyze the proteolysis of IRF3 in virus-infected cells and the specific role of caspase-8 in this process.
Characterization and Optimization of an Eight-Channel Time-Multiplexed Pulse-Shaping System

High-performance optical pulse shaping is paramount to photonics and laser applications for which high-precision optical waveforms must be generated. We investigate the design and performance of a time-multiplexed pulse-shaping (TMPS) system in which optical waveforms from a single pulse-shaping unit are demultiplexed and retimed before being sent to different optical systems. This architecture has the advantages of low cost and low relative jitter between optical waveforms because a single pulse-shaping system, e.g., a high-performance arbitrary waveform generator driving a Mach–Zehnder modulator, generates all the waveforms. We demonstrate an eight-channel TMPS system based on a 1 × 8 LiNbO3 demultiplexer composed of four stages of 1 × 2 Δ β phase-reversal switches. It is shown that optimal demultiplexing, i.e., low insertion loss and high extinction ratio between channels, requires optimization in dynamic operation because of the slow component of the switches’ response. We demonstrate losses lower than 5 dB, extinction ratios of the order of 70 dB for a four-channel system and 50 dB for an eight-channel system, and jitter added by the demultiplexer smaller than 0.1 ps.
Deleterious protein‐altering mutations in the SCN10A voltage‐gated sodium channel gene are associated with prolonged QT

Background Long QT syndrome (LQT) is a pro-arrhythmogenic condition with life-threatening complications. Fifteen genes have been associated with congenital LQT, however, the genetic causes remain unknown in more than 20% of cases. Materials and methods Eighteen patients with history of palpitations, pre-syncope, syncope and prolonged QT were referred to the Yale Cardiovascular Genetics Program. All subjects underwent whole-exome sequencing (WES) followed by confirmatory Sanger sequencing. Mutation burden analysis was carried out using WES data from 16 subjects with no identifiable cause of LQT. Results Deleterious and novel SCN10A mutations were identified in 3 of the 16 patients (19%) with idiopathic LQT. These included 2 frameshifts and 1 missense variants (p.G810fs, p.R1259Q, and p.P1877fs). Further analysis identified 2 damaging SCN10A mutations with allele frequencies of approximately 0.2% (p.R14L and p.R1268Q) in 2 independent cases. None of the SCN10A mutation carriers had mutations in known arrhythmia genes. Damaging SCN10A mutations (p.R209H and p.R485C) were also identified in the 2 subjects on QT prolonging medications. Conclusion Our findings implicate SCN10A in LQT. The presence of frameshift mutations suggests loss-of-function as the underlying disease mechanism. The common association with atrial fibrillation suggests a unique mechanism of disease for this LQT gene.
Practical Alkoxythiocarbonyl Auxiliaries for Iridium(I)‐Catalyzed C−H Alkylation of Azacycles

The development of new and practical 3-pentoxythiocarbonyl auxiliaries for IrI -catalyzed C-H alkylation of azacycles is described. This method allows for the α-C-H alkylation of a variety of substituted pyrrolidines, piperidines, and tetrahydroisoquinolines through alkylation with alkenes. While the practicality of these simple carbamate-type auxiliaries is underscored by the ease of installation and removal, the method's utility is demonstrated in its ability to functionalize biologically relevant l-proline and l-trans-hydroxyproline, delivering unique 2,5-dialkylated amino acid analogues that are not accessible by other C-H functionalization methods.
Convective Processes in the Lower Atmosphere

Progress in understanding convective processes in the lower atmosphere over the past 25 years has come primarily as a result of vastly improved research tools. These tools - better instruments and numerical simulations on supercomputers - have given us a fairly complete view of the structure of boundary-layer convection, if not yet a solution to the “turbulence problem”.
PERC strategy was noninferior to the usual strategy for ruling out PE in low-risk patients in the ED.

Source Citation Freund Y, Cachanado M, Aubry A, et al; PROPER Investigator Group. Effect of the pulmonary embolism rule-out criteria on subsequent thromboembolic events among low-risk emergency dep...
Increasing extent and intensity of thunderstorms observed over the Congo Basin from 1982 to 2016

Abstract Recent studies found a long-term drought and resulting declines in vegetation greenness and canopy water content over the Congo Basin, the second largest rainforest in the world after the Amazon. Since most precipitation in tropical latitudes stems from convection, this paper analyzed 35 years of high-resolution (8 km spatial resolution and 3 h temporal resolution) satellite data to document the long-term trends in the number, size and intensity of thunderstorms activity over the Congo Basin during April, May, and June (AMJ) for the period 1982–2016. Changes in the magnitude and area of cold cloud top brightness temperatures (Tb) at different thresholds were used as a proxy to quantify the number and size of individual thunderstorms at different intensities. We found that the areal extent and intensity of thunderstorms increased over the past 35 years, particularly over Northern Congo Basin, and these changes are consistent with other satellite datasets. Combined with a reanalysis dataset, our work suggests that thunderstorms over the Congo Basin are becoming taller and wider, and likely resulting in a moister (drier) upper (lower) troposphere.
Fluorescence Studies of the Calcium-Dependent Functions of Calmodulin

Calmodulin is a major intracellular Ca2+ receptor in eucaryotic cells. The binding of Ca2+ stabilizes one or more conformations of the calmodulin molecule recognized by calmodulin-dependent enzymes such as cyclic nucleotide phosphodiesterase (Cheung, 1967); adenylate cyclase (Cheung et al., 1975; Brostrom et al., 1975); phosphorylase kinase ([Grand et al., 1981; cf review by Malencik & Fischer, 1983); and myosin light chain kinase (cf reviews by Stull, 1980; Small & Sobieszek, 1980; Perry et al., 1984). Large increases in catalytic activity typically result from the association of these enzymes with the calcium-calmodulin complex. A variety of small non-protein ligands also undergo calcium-dependent interactions with calmodulin. The best known of these are the phenothiazine drugs and other pharmacological agents first described by Levin and Weiss (1977). Since evidence suggests that these molecules recognize parts of calmodulin which are the same as (or closely related to) the association sites for calmodulin-dependent enzymes, they have been embraced as models for the characterization of the enzyme-calmodulin interface. However, the information obtainable from them is necessarily incomplete.
Attaching Names to Objects

The process of attaching names (labels) to objects has been of great interest to philosophers since the days of the Greeks. However, in recent times other philosophical problems have seemed to be more interesting, and the subject of naming has been rather neglected. The few contemporary philosophers who have written about it have, on the whole, been quite unaware that the same problem of naming and fixing a name to a specified object has been one of the foremost concerns of taxonomy, one of the sciences. There is, however, one philosopher, David Hull, who did realize it and who attempted in a series of publications to show to what extent philosophy and taxonomy can help each other by reciprocal illumination. There are issues where the philosopher can help the taxonomist to improve his methods and definitions and others where the taxonomist has worked out methods that do the same for the philosophers.
La prosa de la contrainsurgencia

espanol«La prosa de la contrainsurgencia»replantea el problema de lo politico y presta atencion a axiomas emergentes sobre lo social como conjunto de articulaciones complejas y fragmentarias, constituidas en torno a asimetrias fundamentales, y a una creciente proliferacion de diferencias.La escena es nicaraguense; la reflexion versa sobre las diferentes facetas de la revolucion sandinista examinada post-facto.El recuento pasa por la continuidad del sandinismo; la memoria historica que dicha rubrica representa; y el debate de si la revolucion era socialista o no.Para eso toca puntos neuralgicos relativos a la reforma agraria, el grado de inflacion del decenio, y el tipo de participacion ciudadana.Los textos escritos post-revolucion exponen la situacion critica de la participacion de las mujeres, de jovenes combatientes en la guerra, y de la transicion al neo-liberalismo.El trabajo descarta la idea de una totalidad estructural suturada y la reemplaza por el concepto de articulacion e identidades de sujeto social en flujo constante.Nicaragua se situa dentro de un vasto universo social-global marcado por loshitos de revolucion o guerra, que diolugar o al socialismo o a la social democracia en el mejor de los casos English«The Prose of Counterinsurgency» raises the question of ‘the political’, taking into account emerging theoretical axioms over the social as sets of complex and fragmentary articulations, constituted around fundamental asymmetries and growing proliferation of differences. The scene is Nicaraguan: the reflection is over the different aspects of the Sandinista Revolution examined post-fact. The recount passes review to the continuation of sandinismo, the historic memory that it represents, and the debate on the character of the revolution—socialist or not. For that reason, it examines key points relative to the agrarian reform, the type of inflation during that decade, and forms of citizen participations. Post-revolutionary texts expose the critical situation of women participation, young combatants in the war, and the transition to neo-liberalism. The study discards the idea of a totally sutured structure and replaces it with the concept of articulation and the constant flux of the social subject. Nicaragua is situated within a vast social-global universe, marked by the choice of revolution or war that gave rise to socialism or social democracy in the best of cases.
Corn yield variability on the Des Moines Lobe of Iowa: Assessment of extent and soil-related causes

Precision agriculture techniques are an essential component to modern row crop agriculture in Iowa and can be used to create crop yield variability maps via geographic information systems. The first objective of this thesis was to explore the methodology that could be used to locate significant long-term corn yield variability on the Iowa Des Moines Lobe. A 158-ha site, consisting mainly of Clarion, Nicollet and Webster soil map units and containing multiple years of geo-referenced corn (Zea mays) yield data was selected. A cluster analysis tool was performed to locate spatially consistent corn yield variability (high, low and mean yield clusters). The mean yield of the entire site from 2005 to 2011 was 12052 kg ha-1 compared to the high and low clusters which were 13747 kg ha-1 and 10420 kg ha-1, respectively. It was observed that 12% of the site was consistently variable, of which 82%, occurred within the Clarion. This identification approach could be used as a basis for variable rate management which could increase yield, net profitability and sustainability. The second objective was to explore the relationships of specific soil characteristics associated with the identified variability clusters. High yielding clusters were deeper to maximum depth of mollic colors, higher in total carbon (TC) and total nitrogen (TN) content at 0 to 25 cm, higher in Mehlich 3 phosphorus (M3P) and Mehlich 3 potassium (M3K) content at all depths and higher in clay content at 0 to 25 cm and 26 to 100 cm compared to low yielding clusters. At the 0 to 25 cm depth, 60% of yield variability was associated with TN, M3P and M3K and clay content. These four soil characteristics were positively
Adhesion of Plasma Polymerized Films (A Model Study on Water Sensitivity of Adhesion)

Failures of coatings or thin polymer films applied to different kinds of materials, such as metals, ceramics, and polymers, due to the influence of water (liquid or vapor) are related to the affinity of water to the substrate surface and to the polymer coating. Therefore, there is no direct correlation between dry adhesive strength and wet adhesive strength. This situation can be demonstrated by using vacuum deposition of polymers by Parylene polymerization and/or plasma polymerization of organic monomers. Because of unique polymerization mechanisms, plasma polymers can be utilized to provide ultrathin primer coatings which adhere well to metals and ceramics and convert hydrophilic nature to more hydrophobic surface and improve the overall water resistivity of adhesion of coatings.
CRSPR/CAS 9 and Human Therapeutics.

The CRSPR/Cas 9 adaptive bacterial immune system, operationalized as the Cas9/guide RNA platform, has garnered considerable attention as a potentially transformative technology in the creation and delivery of novel gene therapies for genetic disease. Compared with earlier technologies, the system offers greater precision and ease of use and offers promise for both ex vivo manipulation of somatic cells and in vivo editing through viral vectors, as well as, possibly, germ line alteration through in vitro use in human embryos. Potential applications include the treatment of sickle cell disease, retinitis pigmentosa, and β thalassemia. These applications are notable for not only their previous intractability to treatment but also their potential to address some large health disparities with regard to ethnic variation in the target population. The first clinical trials for the use of CRSPR-based therapies, for cancer, were reported in China in 2016. Research has …
Open nanofluidic films with rapid transport and no analyte exchange for ultra-low sample volumes

Moving to ultra-low ( 500 nL min-1 per square of film; (4) ultra-simple roll-to-roll fabrication; (5) stable and bio-compatible super-hydrophilicity for weeks in air by peptide surface modification. Validation includes both detailed in vitro characterization and in vivo validation with sweat transport from the human skin. Sampling times (skin-to-sensor) of <3 min were achieved, setting new benchmarks for the field of wearable sweat sensing. This work addresses significant challenges for sweat biosensing, or for any other nano-liter regime (<100 nL) fluid sampling and sensing application.
A Model for Hyper-Elastic Material Behavior Under Thermal Aging With an Application to Natural Rubber

Numerous hyper-elastic theoretical material models have been proposed over the past 60 years to capture the stress-strain behavior of large deformation incompressible isotropic materials. Among them, however, only few models have considered the thermal aging effect on model parameters. Having a simple, closed-form equation that includes the effect of aging temperature and time in describing the stress-strain behavior could facilitate fatigue analysis and life time prediction of rubber-like materials. In this vein, this paper defines a new and simple Weight Function Based (WFB) model that describes hyper-elastic materials’ behavior as a function of aging time and temperature variations. More than 130 natural rubber specimens were thermally aged in an oven and tested under uni-axial loading to observe their stress-strain behavior at various temperatures and aging times. The temperature ranged from 76.7 °C to 115.5 °C, and the aging time from zero to 600 hours. The proposed WFB model is based on the Yeoh model and basic continuum mechanics assumptions, and it was applied to the tested natural rubber materials. Moreover, it was verified against Treloar’s historic tensile test data for uni-axial tension of vulcanized natural rubber material, and also compared to the Ogden and the Yeoh models. A non-linear least square optimization tool in Matlab was used to determine all hyper-elastic material model parameters and all other fitting purposes. The proposed model has better accuracy in fitting Treloar’s data compared to the Ogden and the Yeoh models using the same fitting tool under the same initial numerical conditions.Copyright © 2018 by ASME
Origins of Vorticity in a Simulated Tornadic Mesovortex Observed during PECAN on 6 July 2015

AbstractTo better understand and forecast nocturnal thunderstorms and their hazards, an expansive network of fixed and mobile observing systems was deployed in the summer of 2015 for the Plains Ele...
RECALLED ICD GENERATORS IN THE NCDR-ICD REGISTRY: OUTCOMES AND SURVEILLANCE IMPLICATIONS

The consequences of ICD generator recalls are not well defined. We compared complications from generator exchange (GE) of malfunctioning and/or recalled ICD generators vs elective GE. We also compared the operator-reported device malfunction with reasons for FDA recall. GE in the NCDR ICD Registry
Laura Edmondson. Performing Trauma in Central Africa: Shadows of Empire.

In Performing Trauma in Central Africa: Shadows of Empire, Laura Edmondson illustrates the pervasive effects of western appetites for African suffering – what she calls the “empire of trauma” – on ...
Abstract 2878: CRISPR-Cas9 screens identify the nuclear export factor NXT1 as a novel therapeutic target inMYCN-amplified neuroblastoma

Pediatric cancers, such as neuroblastoma, have a relative lack of oncogenic mutations and the known drivers of these cancers are largely transcription factors, a target class notoriously difficult to “drug.” In order to identify novel therapeutic targets for high-risk, MYCN-amplified neuroblastoma, we employed functional genomic screening using a CRISPR-Cas9 approach. We generated genome-scale CRISPR dependency data to identify a candidate gene list of 197 putative genetic dependencies in neuroblastoma. We next created a focused sgRNA library targeting these genes and performed time-course dropout screens using CRISPR and CRISPRi and Annexin-V-based positive-selection cell death screens in four MYCN-amplified neuroblastoma cell lines. We also screened this library in vivo in two xenograft models of MYCN-amplified neuroblastoma. At the intersection of these screens, we identified the nuclear export factor NXT1 as a top candidate for therapeutic development in neuroblastoma. NXT1 scores as a strong dependency using both CRISPR and CRISPRi, is strongly enriched in our Annexin-V based positive selection cell death screen and scores in our in vivo screen. We have validated that NXT1 is indeed a genetic dependency in neuroblastoma in low-throughput and that NXT1 loss induces apoptosis in these cell lines. We were next interested in identifying biomarkers of dependency on NXT1, and by integrating RNAseq data with CRISPR dependency data, we identified low expression of NXT2, a paralog of NXT1, as the top predictive feature of NXT1 dependency. Importantly, while NXT1 itself is not currently druggable, inhibitors against another nuclear export protein, CRM1, are currently in Phase II clinical trials, demonstrating this class of proteins has the potential to be effectively drugged. Together, we show that CRISPR-Cas9 functional screens can be used to identify new therapeutic targets, particularly in diseases that lack “druggable” oncogenic drivers, such as many pediatric cancers. Citation Format: Clare F. Malone, Neekesh V. Dharia, Guillaume Kugener, Brenton Paolella, Michael Rothberg, Mai Abdusamad, Alfredo Gonzalez, Nancy Dumont, Scott Younger, David Root, Francisca Vazquez, Kimberly Stegmaier. CRISPR-Cas9 screens identify the nuclear export factor NXT1 as a novel therapeutic target in MYCN-amplified neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2878.
"Not in my name": the anti-racist praxis of Mab Segrest & Minnie Bruce Pratt.

Minnie Bruce Pratt (1946-) and Mab Segrest (1949-) are white middle-class lesbians that both came of age during the classical phase of the Civil Rights Movement in rural Alabama. Today, they are co...