cssi/SciSciGPT-SciSciNet huggingface dataset:
Engineered tRNA suppression of a CFTR nonsense mutation

Ten percent of human diseases are caused by nonsense mutations that lead to premature truncation of the protein reading frame. Small molecules that promote read-through of such PTC have significant clinical promise but current iterations suffer from low in vivo efficacy and the nonselective amino acid incorporation. Alternatively, while gene-modifying approaches, such as CRISPR/Cas9, represent a long-term solution, such cures are likely to be far off from reaching the clinical setting. Therefore, building on previous work by our group and others, we describe a tRNA engineering approach that enables the conversion of an in frame stop to the naturally occurring amino acid, thus rescuing the full-length wild type protein. Data is presented demonstrating the functionality of the the approach with the rescue of CFTR W1282X, a human mutation that causes cystic fibrosis (CF). The stringency of the approach is confirmed by mass spectrometry in a model protein indicating the encoding of only tryptophan at the TGA suppression site. The data describe the first use of an edited tRNA to repair a CF causative mutation and serve a proof of principle for the eventual use of codon-edited tRNA for the therapeutic rescue of PTC disease codons.
New and Future Trends in Radiopharmaceuticals

Among all of the diagnostic imaging specialties, none is so dependent on the development of new agents as nuclear medicine. Changes in instrumentation lead to dramatic improvements in the diagnostic capabilities of radiographic devices including ultrasound and magnetic resonance. Similar developments in instrumentation have a very profound effect on nuclear medicine performance as well, but only if the appropriate diagnostic agents are available.
Insights from molecular dynamics simulations for computational protein design

A grand challenge in the field of structural biology is to design and engineer proteins that exhibit targeted functions. Although much success on this front has been achieved, design success rates remain low, an ever-present reminder of our limited understanding of the relationship between amino acid sequences and the structures they adopt. In addition to experimental techniques and rational design strategies, computational methods have been employed to aid in the design and engineering of proteins. Molecular dynamics (MD) is one such method that simulates the motions of proteins according to classical dynamics. Here, we review how insights into protein dynamics derived from MD simulations have influenced the design of proteins. One of the greatest strengths of MD is its capacity to reveal information beyond what is available in the static structures deposited in the Protein Data Bank. In this regard simulations can be used to directly guide protein design by providing atomistic details of the dynamic molecular interactions contributing to protein stability and function. MD simulations can also be used as a virtual screening tool to rank, select, identify, and assess potential designs. MD is uniquely poised to inform protein design efforts where the application requires realistic models of protein dynamics and atomic level descriptions of the relationship between dynamics and function. Here, we review cases where MD simulations were used to modulate protein stability and protein function by providing information regarding the conformation(s), conformational transitions, interactions, and dynamics that govern stability and function. In addition, we discuss cases where conformations from protein folding/unfolding simulations have been exploited for protein design, yielding novel outcomes that could not be obtained from static structures.
Partnership for Education: Students’ perceptions of a graduate cohort program conducted within an organizational environment

The term “cohort” in academic and non-academic settings refers to a group of students who begin a program of study at the same time and progress through a specified sequence of courses until completion. In recent years, academic institutions have begun to offer customised courses and degree programs in the cohort format at a client organisation’s facilities. Although these educational partnerships provide convenience and appear to offer advantages not available in traditional formats, there is little research-based guidance on how to improve the effectiveness of these programs from the learner’s perspective. This study describes and analyses the perceptions of U. S. adult students in an educational partnership between a State of Georgia university (GU) and a State of Georgia Health System (GHS) that awarded a Masters in Business Administration with a specialisation in Healthcare Management Degree program. This investigation led to a set of recommendations for improving the program design for future cohorts. A descriptive, case study approach was used, including evaluations, surveys, focus groups, individual interviews, and standardised test scores. Routine, end-of-course evaluations and special cohort-only surveys were analysed to develop focus group interview questions and individual participant interviews. Major Field Test (MFT) scores were used to compare cohort students with other non-cohort GU majors and national score averages. The primary conclusions reached in this study were that the cohort students believed that the program design was good but that there were problems that needed to be addressed in future cohort programs. Major recommendations for improvement addressed the issues of curriculum focus, course scheduling, group dynamics, communications, organisational involvement, and recognition of graduates.
Climate Change Constrains the Efficiency Frontier When Managing Forests to Reduce Fire Severity and Maximize Carbon Storage

Abstract Pareto efficiency frontiers are ideal analytical tools for evaluating likely shifts in the production of forest ecosystem services under climate change. In the context of multi-objective forest management, these frontiers, or the set of non-dominated solutions for a set of objectives at varying levels of output, provide quantitative measures of trade-offs between competing ecosystem services and changes in the best-possible management outcomes for different climate change scenarios. We used outputs from a forest growth-and-yield model that simulated wildfire and management to examine three types of Pareto frontier analyses: 1) carbon storage maximization under changing budgetary constraints with and without wildfire effects, 2) minimization of undesirable wildfire effects under changing budgetary constraints, and 3) minimization of undesirable wildfire effects at varying constrained carbon storage levels. We found that over 45 years climate change reduced the average amount of carbon stored, whether or not we simulated a wildfire on the 23,204 ha study area despite our best management efforts. Climate change also adversely affected the trade-off rate, or slope of the frontiers, between carbon storage and wildfire effects. We illustrate how the application of a methodology typically used in economics can reveal insights in forest ecosystem management otherwise hidden to decision-makers.
Small Molecule Inhibitors of ALK

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that has attracted a great deal of attention due to its oncogenic potential and essential role in the pathogenesis of a wide variety of human cancers, such as anaplastic large cell lymphomas (ALCLs), non-small cell lung cancer (NSCLC), breast cancer, colorectal cancer, neuroblastoma, and ovarian cancer. Despite the remarkable clinical success of crizotinib (Xalkori), the first ALK inhibitor approved in 2011 for the treatment of NSCLC, the emergence of resistance mutations frequently causes relapse in patients. As a result, a variety of second and third generation ALK inhibitors have been developed to overcome these mutations. This chapter presents an overview of the hit-to-drug evolution strategies as well as the biological activities of several second and third generation ALK inhibitors.
Maroons and Mi'kmaq in Nova Scotia, 1796-1800

Forcibly relocated by the Jamaican government, the Maroons of Trelawney Town, Jamaica, reached Halifax in July 1796. Lieutenant-Governor John Wentworth, former loyalist governor of New Hampshire, experimented with integrating and converting these 150 uprooted black families, refugees of war. His self-congratulatory benevolence created and extended the fractured relationships among black and Aboriginal communities in the region. This article helps demonstrate the limits of British paternalism and the far-reaching consequences of distinguishing people of African ancestry from Aboriginal people.
Integrating future scenario‐based crop expansion and crop conditions to map switchgrass biofuel potential in eastern Nebraska, USA

Switchgrass (Panicum virgatum) has been evaluated as one potential source for cellulosic biofuel feedstocks. Planting switchgrass in marginal croplands and waterway buffers can reduce soil erosion, improve water quality, and improve regional ecosystem services (i.e., it serves as a potential carbon sink). In previous studies, we mapped high risk marginal croplands and highly erodible cropland buffers that are potentially suitable for switchgrass development, which would improve ecosystem services and minimally impact food production. In this study, we advance our previous study results and integrate future crop expansion information to develop a switchgrass biofuel potential ensemble map for current and future croplands in eastern Nebraska. The switchgrass biomass productivity and carbon benefits (i.e., NEP: net ecosystem production) for the identified biofuel potential ensemble areas were quantified. The future scenario-based (“A1B”) land use and land cover map for 2050, the U.S. Geological Survey crop type and Compound Topographic Index (CTI) maps, and long-term (1981–2010) averaged annual precipitation data were used to identify future crop expansion regions that are suitable for switchgrass development. Results show that 2,528 km2 of future crop expansion regions (~3.6% of the study area) are potentially suitable for switchgrass development. The total estimated biofuel potential ensemble area (including cropland buffers, marginal croplands, and future crop expansion regions) is 4,232 km2 (~6% of the study area), potentially producing 3.52 million metric tons of switchgrass biomass per year. Converting biofuel ensemble regions to switchgrass leads to potential carbon sinks (the total NEP for biofuel potential areas is 0.45 million metric tons C) and is environmentally sustainable. Results from this study improve our understanding of environmental conditions and ecosystem services of current and future cropland systems in eastern Nebraska and provide useful information to land managers to make land use decisions regarding switchgrass development. This article is protected by copyright. All rights reserved.
The case for making organ transplant waitlists public to increase donation rates: is it possible?

Aquest article revisa l'estreta relacio entre la negativa a donar organs i la percepcio de que els mecanismes d'assignacio no sempre estan motivats per necessitats mediques, sino per factors aparentment injustos com son l'estatus, els ingressos, l'origen etnic o les connexions individuals. La falta d'organs per a trasplantaments es un dels majors obstacles que han d’afrontar els sistemes de trasplantament a tot el mon i el trasplantament es l'unic camp tecnologicament avancat de la medicina que depen totalment de la comprensio i el suport public, la qual cosa ofereix fortes raons per augmentar-ne la transparencia i la confianca de la comunitat fent que les llistes d'espera siguin publiques.
An enhanced active DC-flux injection based approach for thermal monitoring of induction machines with direct torque control schemes

This paper proposes an enhanced approach to estimate the stator winding temperature based on active DC flux injection for induction machines with two representative direct torque control (DTC) schemes, the conventional hysteresis-based DTC and the deadbeat DTC. In this method, the stator resistance is regarded as the indicator of its temperature, and is estimated by applying offsets to the flux controllers in the DTC schemes thus injecting DC currents and voltages into the stator windings for short periods of time. To compensate the low-frequency pulsating torque caused by the DC fluxes and currents that is inherent in conventional DC-signal-injection-based methods, second-order harmonic fluxes that generate the opposite low-frequency pulsating torque are injected into the stator windings at the same time in both the conventional hysteresis-based and deadbeat DTC schemes. Experimental results show that the proposed method can accurately estimate the stator winding temperatures and effectively eliminate the pulsating torque thus minimizing the impacts of DC-signal injection on the normal operation of the induction motors.
Risk behavior-based trajectory prediction for construction site safety monitoring

AbstractConstruction sites are often described as some of the most hazardous work environments due to the unscripted nature of tasks which puts workers and equipment in close proximity, potentially...
Kidney Diseases Associated with Human Immunodeficiency Virus Infection.

Kidney disease, which is a common complication of HIV infection and its treatment, may shorten the lifespan of affected patients. This review considers the breadth of conditions that may affect the kidneys in persons with HIV infection.
“Military Engagement with a Responsible Stakeholder: The Taft Administration and Qing Imperial China”

In the early 20 th Century, the Taft administration and the Qing Empire developed a working relationship that went beyond transactional “Dollar Diplomacy” to include military engagement. Military and official visits, arms contracts, and opportunities for military education signaled a shift away from both President Theodore Roosevelt’s pro-Japanese policies and the Qing Empire’s isolation from the international order. The massacre of over three hundred Chinese at Torreon, Mexico in May 1911 inadvertently assisted this rapprochement, which presented the Qing Dynasty with an opportunity to demonstrate power and influence when it dispatched the cruiser Hai Qi to the Caribbean. The swift response to the massacre shows that Qing diplomats were capable of using an integrated and mutually reinforcing set of legal, diplomatic, and military tools to attain their political objectives. The incident also demonstrates that the Taft administration was willing to allow a foreign military vessel to coerce Mexico for monetary gain in a direct violation of the Monroe Doctrine. The Qing Empire’s very effective use of gunboat diplomacy revealed a highly competent Chinese government, as well as how U.S. officials arranged a sophisticated rapprochement with Imperial China in the 1909–1912 period.
Micromorphological evaluation of loess deposits and paleosols on Crowley's Ridge, Arkansas, U.S.A.

Abstract West, L.T. and Rutledge, E.M., 1994. Micromorphological evaluation of loess deposits and paleosols on Crowley's Ridge, Arkansas, U.S.A. In: A.J. Ringrose-Voase and G.S. Humphreys (Editors), Soil Micromorphology: Studies in Management and Genesis. Proc. IX Int. Working Meeting on Soil Micromorphology, Townsville, Australia, July 1992. Developments in Soil Science 22, Elsevier, Amsterdam, pp. 265–276.
NEUROTOXIC EFFECTS OF HEAVY METALS AND METALLOIDS

Publisher Summary This chapter discusses several heavy metals and metalloids and their neurotoxic effects in producing neural dysfunction. The widespread use of compounds containing heavy metals and metalloids has not only led to occupational hazards but has also superimposed the problems of environmental pollution. These materials are general protoplasmic poisons and noncompetitively inhibit a number of enzyme-mediated reactions. Other biochemical effects—such as protein denaturation, membrane alteration, and change in acid base and ionic equilibrium—may also contribute to neural toxicity. Secondary effects on neural tissue also result from toxic action on cerebral blood vessels and on other parenchymal organs—such as the liver, kidney, and hematopoietic tissue. The use of arsenic metalloid in insecticide sprays results in contamination of fruits and vegetables. As in the case of the heavy metals, much of the toxic effect of arsenicals relates to an ability to bind sulfhydryl radicals and to interfere with enzyme activity.
Bombing Wichita: How the bombing campaigns of World War II spurred production and change in Wichita, Kansas

Far above Germany, seven men fly. Their jobs are all different and imperative to the success of their mission. Hundreds of other planes fly beside them. All are focused on the task and trust in the rest of the crew and in their plane. Once the target is sighted, tons of bombs are released. They see the explosions and are elated in another mission completed. What they did not see was the family home the bombs destroyed, or the family members that lost their lives to the horrors of air warfare. The military gave justifications for this new method of war. Perhaps in their hearts, the pilots and crew felt bad for those who perished. However, they are at war and did whatever needed to be done to win. Thousands of miles away, different civilians faced disparate stresses. These civilians lived in Wichita, Kansas and they were imperative to the production of airplanes for World War II. The Boeing-Wichita plant is an important case study of war production. It was the largest plant located in Kansas and built the most iconic aircraft of World War II. The war production transformed Wichita’s people, infrastructure, future and added stress to a considerable number of those in Wichita; however, those stresses did not include wrestling with the morality of bombing civilians of belligerent nations.
Payoff Optimization Through Wireless Network Virtualization for IoT Applications: A Three Layer Game Approach

Performance of wireless networks for Internet of Things (IoT) is suffering from exponential growth of lightweight hand-held and smart IoT devices as well as the data flow in the network. Static assignment of wireless resources is creating bottleneck to the further development of emerging applications, including IoT and cyber-physical systems. Wireless network virtualization through slicing of primary wireless resources is regarded as an emerging approach for enhancing overall network performance to solve the bottleneck problem for those emerging applications. In this paper, we study wireless virtualization where a three-layer game is formulated for wireless infrastructure providers (WIPs), mobile virtual network operators (MVNOs), and IoT devices (or end users). In the proposed three-layer game, players play sequentially to find out their optimal strategies. With the help of a controller, WIPs divide and reconfigure their RF bands to sublease frequency slices to MVNOs based on their service-level-agreement. MVNOs let end users use their subleased frequency slices. For the game, we present a unique optimal solution that facilitates a tradeoff between quality of service of end users, payoffs of MVNOs and payoff of WIPs. We also present a necessary condition and closed form for the existence of an equilibrium in the game. Furthermore, performance of the proposed approach is evaluated using numerical results which show that the payoffs of WIPs and MVNOs are maximized while offering competitive price for the subleased RF spectrum for their users.
Saving Mothers, Giving Life: A Systems Approach to Reducing Maternal and Perinatal Deaths in Uganda and Zambia

The 5-year public-private partnership boldly addressed maternal mortality in Uganda and Zambia using a systems approach at the district level to avoid delays in women seeking, reaching, and receiving timely, quality services. This supplement provides details on the Saving Mothers, Giving Life partnership and approach, including the model, impact, costs, and sustainability.
Application of the least-squares method to elastic and photoelastic calibration of orthotropic composites

New experimental methods continue to be proposed for determining the in-plane elastic constants of orthotropic composite materials, as no single method has been found completely satisfactory. In particular, the in-plane shear modulus is difficult to measure. In this paper, an orthotropic half-plane subjected to a concentrated edge load is proposed as a calibration specimen. Photoelastic calibration of orthotropic-birefringent composites is also difficult due to the need to conserve the commercially unavailable, difficult-to-make model materials and the absence of many closed-form solutions. In this paper, the orthotropic half-plane specimen is proposed for photoelastic calibration of birefringent-orthotropic model materials also. For elastic and photoelastic calibration of orthotropic materials, the least-squares procedure is used for processing the experimental data.
Block-wise and trial-wise analyses of the late positive potential reveal distinct affective trajectories as a function of neuroticism.

Abstract The late positive potential (LPP), an event-related potential that is modulated by affective stimuli, is often employed as an objective measure of momentary emotional reactivity in affective neuroscience research. A wide range of tasks are used to elicit the LPP, yet relatively few studies assess how task-specific methodological differences influence observed effects on LPP amplitude. The present study tested whether the LPP systematically varies across repeated blocks of affective stimuli in terms of block-wise averages and trial-wise slopes, as well as if this variability relates to trait affective style. Participants (N = 112) completed a passive-viewing task designed to assess carry-over effects from one fixed valence block to the next. Rather than single scores for each image type averaged across all trials, as is typically done, the LPP was investigated first as averages across single blocks organized by valence and arousal categories and then trial-wise within these blocks. Traditional analyses and multilevel modeling procedures were employed to investigate effects. Results revealed that average LPP amplitude increased for the second versus the first blocks for affective but not neutral images. Moreover, trial-wise variation in the LPP systematically related to trait affective style: neuroticism moderated slopes of reactivity to pleasant and unpleasant images and produced affective carry-over effects for those higher in neuroticism. Together, results suggest that LPP amplitude is systematically modulated by block sequence, which could explain discrepancies across studies. Furthermore, block-wise averages capture only a portion of reactivity, obscuring trial-wise dynamics that are more closely aligned with theoretical frameworks of emotion.
Innate IFNγ is essential for systemic Chlamydia control while CD4 T cell-dependent IFNγ production is highly redundant in the female reproductive tract

Abstract Protective immunity to the obligate intracellular bacterium Chlamydia is thought to rely on CD4 T cell-dependent IFNγ production. Nevertheless, whether IFNγ is produced by other cellular source during Chlamydia infection and how CD4 T cell-dependent and -independent IFNγ contribute differently to host resistance has not been carefully evaluated. In this study, we dissect the requirements of IFNγ produced by innate immune cells and CD4 T cells for resolution of Chlamydia muridarum female reproductive tract (FRT) infection. After C. muridarum intravaginal inoculation, IFNγ-deficient and T cell-deficient mice exhibited opposite phenotypes for survival and bacterial shedding at the FRT mucosa, demonstrating the distinct requirements for IFNγ and CD4 T cells in host defense against Chlamydia. In Rag-deficient mice, IFNγ produced by innate lymphocytes (ILCs) accounted for early bacterial containment and prolonged survival in the absence of adaptive immunity. Although group I ILCs are potent IFNγ producers, we found that mature NK cells and ILC1 were not the sole source for innate IFNγ in response to Chlamydia. T cell adoptive transfer experiments revealed that WT and IFNγ-deficient CD4 T cells were equally capable of mediating effective bacterial killing in the FRT during the early stage of Chlamydia infection. Together, our results revealed that innate IFNγ is essential for preventing systemic Chlamydia dissemination, whereas IFNγ produced by CD4 T cells is largely dispensable at the FRT mucosa.
Pediatric Residents’ Sense of Meaning in Their Work: Is This Value Related to Higher Specialty Satisfaction and Reduced Burnout?

Abstract Objective Physician wellness is frequently measured as the absence of burnout, rather than the perception of meaningful work. This study of pediatric residents aimed to test the hypothesis that their sense of meaning at work is associated positively with specialty satisfaction and negatively with burnout. Methods In June 2018, we surveyed residents at a large urban pediatrics program, using the Work and Meaning Inventory (WAMI), the Global Specialty Satisfaction measure, and a single-item burnout measure. Residents were surveyed at the end of their intern, second or third/fourth year. We compared resident responses to outcome measures by year, gender, race, and type of program (pediatrics and medicine-pediatrics). We assessed the associations between WAMI scores and specialty satisfaction using linear regression and between WAMI scores and burnout using logistic regression, both adjusted for residency year and characteristics. Results The survey was completed by 119/154 (77.3%) residents. Mean WAMI score was 40.6 ± 5.6 (standard deviation), mean specialty satisfaction score was 11.9 ± 2.4, and 48.7% (58/119) of residents reported burnout with no significant differences in scores by residency year, gender, race, or type of program (all P > .05). Residents’ WAMI scores were positively associated with specialty satisfaction (r = +0.57, P Conclusions Pediatric residents’ sense of meaning at work was significantly positively associated with specialty satisfaction and negatively associated with burnout. We recommend that efforts to improve resident wellness focus on interventions to foster meaning in work, such as supporting team cohesion and autonomy in job design.
Empathy, gender, and prosocial behavior

Abstract This paper examines how empathy is associated with gender differences in prosocial behavior in some economic games. Examining dictator, charitable giving, public goods, and trust games, we find that accounting for empathy eliminates the significance of gender differences in prosocial behavior in all four games. When the data are pooled from all games, the reduction in the female coefficients are significant after including either total empathy or empathic concern. The strong effect of empathy on prosocial behavior in the four games persists with controls for college major and demographics. This pattern replicates itself only with empathic concern, not the other empathy subscales. We conclude that measured gender differences in prosocial behavior in the games are not due wholly to sex per se, but at least partially to personality traits such as empathy that both sexes share, and that the most empathic men act as prosocially as do women.
Machine-Learning-based Advanced Dynamic Security Assessment: Prediction of Loss of Synchronism in Generators

This paper proposes a machine-learning-based advanced online dynamic security assessment (DSA) method, which provides a detailed evaluation of the system stability after a disturbance by predicting impending loss of synchronism (LOS) of generators. Voltage angles at generator buses are used as the features of the different random forest (RF) classifiers which are trained to consecutively predict LOS of the generators as a contingency proceeds and updated measurements become available. A wide range of contingencies for various topologies and operating conditions of the IEEE 118-bus system has been studied in offline analysis using the GE positive sequence load flow analysis (PSLF) software to create a comprehensive dataset for training and testing the RF models. The performances of the trained models are evaluated in the presence of measurement errors using various metrics. The results reveal that the trained models are accurate, fast, and robust to measurement errors.
Using standardized exams for formative program evaluation

Abstract Systematic program evaluation is important for assessing nursing program quality and achievement of outcomes. Both summative and formative program evaluation have unique value and purpose, but most program evaluation literature to date has focused on summative methods. The purpose of this article is to describe a formative program evaluation method using standardized exam data that was established by an assessment and evaluation committee in a pre-licensure baccalaureate nursing program during the COVID-19 pandemic. Suggestions for how to use the results to support student achievement of program learning outcomes and program-level attainment of benchmarks are discussed.
Responding to the Challenges of Contextual Change and Legal Dynamism in Interpreting the Fourth Amendment

Granting for purposes of argument the general theoretical case for interpreting constitutional text according to some version of the original understanding, this contribution to the University of Mississippi's 2011 Fourth Amendment symposium argues that consulting founding-era practices at the particular level is not a faithful approach to the original understanding. I develop two lines of objection to specific-practices originalism (SPO). I call one the contextual critique and the second the dynamism critique. The constitutional text was situated in the context of eighteenth-century institutions and doctrines that disappeared in the nineteenth century. The utter disappearance of the context means that we just don’t know what the founders expected the Fourth Amendment to prohibit, or permit, in a radically different legal and technological environment. The degree of privacy and liberty in 1791 were a product of the contemporary criminal justice system, the economic and technological social circumstances, and the legal regime that limited search-and-arrest powers. The rules of 1791 would have different consequences for liberty and security in a society like today’s, with full-time proactive police and modern technology.The dynamism critique points out that the 1791 rules of search-and-seizure were not static. Tort law was the legal regime regulating search-and-arrest powers. Illegal detention gave rise to actions for false arrest or false imprisonment. Illegal entries of private premises gave rise to trespass suits. But common law can change. Precedents can be overruled, and new factual contexts require debatable applications of old principles. Most dramatically, common law rules can be trumped by statutes.If the reasonableness clause perpetuates all the specific 1791 tort rules, the force of the contextual critique becomes overwhelming. If, however, the clause incorporates common law rules subject to plenary statutory revision, the constitutional provision is nugatory. Either the Fourth Amendment freezes search-and-seizure law in the form it had before the advent of modern police and modern technology, or it permits any search or arrest authorized by statute. Some search for principled middle ground seems in order. The interpretive mode most faithful to the original understanding is “aspirational balance of advantage originalism,” a mode practically very similar indeed to competing approaches such as common-law constitutionalism or legal process theory.
Rapid and asymmetric divergence of duplicate genes in the human gene coexpression network.

While gene duplication is known to be one of the most common mechanisms of genome evolution, the fates of genes after duplication are still being debated. In particular, it is presently unknown whether most duplicate genes preserve (or subdivide) the functions of the parental gene or acquire new functions. One aspect of gene function, that is the expression profile in gene coexpression network, has been largely unexplored for duplicate genes. Here we build a human gene coexpression network using human tissue-specific microarray data and investigate the divergence of duplicate genes in it. The topology of this network is scale-free. Interestingly, our analysis indicates that duplicate genes rapidly lose shared coexpressed partners: after approximately 50 million years since duplication, the two duplicate genes in a pair have only slightly higher number of shared partners as compared with two random singletons. We also show that duplicate gene pairs quickly acquire new coexpressed partners: the average number of partners for a duplicate gene pair is significantly greater than that for a singleton (the latter number can be used as a proxy of the number of partners for a parental singleton gene before duplication). The divergence in gene expression between two duplicates in a pair occurs asymmetrically: one gene usually has more partners than the other one. The network is resilient to both random and degree-based in silico removal of either singletons or duplicate genes. In contrast, the network is especially vulnerable to the removal of highly connected genes when duplicate genes and singletons are considered together. Duplicate genes rapidly diverge in their expression profiles in the network and play similar role in maintaining the network robustness as compared with singletons. Contact:kdm16@psu.edu Supplementary information: Please see additional files.
The neuronal t-SNARE complex is a parallel four-helix bundle

Assembly of the soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) complex is an essential step for neurotransmitter release in synapses. The presynaptic plasma membrane associated proteins (t-SNAREs), SNAP-25 (synaptosome-associated protein of 25,000 Da) and syntaxin 1A may form an intermediate complex that later binds to vesicle-associated membrane protein 2 (VAMP2). Using spin labeling electron paramagnetic resonance (EPR), we found that the two t-SNARE proteins assemble into a parallel four-helix bundle that consists of two identical syntaxin 1A components and the N-terminal and C-terminal domains of SNAP-25. Although the structure is generally similar to that of the final SNARE complex, the middle region of the helical bundle appears more flexible in the t-SNARE complex. Such flexibility might facilitate interactions between VAMP2 and the t-SNARE complex.
Improved anti-tumor activity and safety of interleukin-13 receptor targeted cytotoxin by systemic continuous administration in head and neck cancer xenograft model.

IL-13 receptor (IL-13R) targeted cytotoxin, IL13-PE38QQR, has been shown to have very potent anti-tumor activity to IL-13R-expressing head and neck tumor cells in vitro and in vivo. However, its effect is limited in aggressive tumors. To further improve the anti-tumor activity and safety of IL-13 cytotoxin, we employed continuous infusion technique in animal model of head and neck cancer. We surgically implanted continuous infusion (CI) pump intraperitoneally that released drug for 7 days, and its anti-tumor effect was evaluated. A comparison was made for antitumor activity and safety with intravenously (IV) administered IL-13 cytotoxin in a head and neck (KCCT873 and HN12) subcutaneous (SC) xenograft tumor models in nude mice. Vital organ toxicities were assessed by histologic examinations and blood serum chemistry analyses. The 50 or 75 µg/kg/day for 7 days of IL-13 cytotoxin either by IV or CI administration did not show any difference in safety or anti-tumor activity. IV administration of 150 or 200 µg/kg/day of IL-13 cytotoxin for 7 days was lethal to nude mice, whereas 200 µg/kg/day X 7 days of CI administration was highly effective in the regression of established tumors without any toxicities. Additionally, CI administration of IL-13 cytotoxin (200 µg/kg/day) showed growth inhibition of larger HN12 tumors in nude mice. With a CI schedule, IL-13 cytotoxin can be systemically administrated at approximately twice the dose otherwise given by daily IV bolus administration.
Abstract T MP25: Development of Patient Specific Computational Fluid Dynamics Model of Intracranial Arterial Stenosis

Introduction: Intracranial atherosclerotic steno-occlusive disease (ICASD) is a significant cause of stroke worldwide. A better understanding of the role of hemodynamic factors in the progression of ICASD is fundamental for the development of future treatment strategies. Prior studies have been limited to estimations of wall shear stress (WSS), turbulent kinetic energy (TKE), and flow velocity (FV) at single physiological states. We present a modeling technique for measuring hemodynamic parameters across a cardiac cycle using patient-specific vessel geometry and boundary conditions. Methods: The geometry was obtained from a rotational angiogram of the symptomatic lesion. Transcranial Doppler (TCD) was used to digitally record the cerebral blood flow velocity (CBFV). The MOCAIP algorithm was used to calculate dominant, artifact-free CBFV waveforms for each vessel. The mesh and boundary conditions were imported into the ANSYS: Simulation Technology software as a non-deformable mesh containing a Newtonian fluid with molar mass 64500g/mol, density 1.06g/cc, and viscosity 0.035 centipoise. A dynamic state (DS) simulation of one full cardiac cycle with 25ms timesteps and steady state (SS) simulations using the velocities at the systolic peak were performed. WSS, TKE, and FV within the stenosis were measured and compared between DS and SS simulations. Results: When compared with the DS simulation, the mean WSS of the SS simulation was significantly higher (SS 30.6Pa DS 30.0Pa, p<0.0005). There were no significant differences between TKE (SS 0.074m2/s2 DS 0.073m2/s2) or FV (SS 2.68m/s DS 2.71m/s). Conclusion: Incorporating individual-specific boundary conditions based on CBFV TCD measurements with patient-specific geometry intracranial arterial modeling is feasible and adds a spectrum of dynamic data that can significantly differ from SS simulations. ![][1] [1]: /embed/graphic-1.gif
Role of spectrally varying mount properties in influencing coupling between powertrain motions under torque excitation

The influence of spectrally varying mount properties (including stiffness and damping) on the dynamics of powertrain motions is analytically examined. To overcome the deficiency of the direct inversion method (limited to only the frequency domain analysis), two methods are developed that describe the mount elements via a transfer function (in Laplace domain) or analogous mechanical model. New analytical formulations are verified by comparing the frequency responses with numerical results obtained by the direct inversion method (based on Voigt type mount model). Eigensolutions and transient responses of a spectrally varying mounting system are also predicted from new models. Based on complex eigenstructure, new coupling indices, including modal kinetic energy fractions, are defined for each method. Complex eigenvalue problem formulation with spectrally varying properties provides a closer match with measured natural frequencies than the real eigensolution with frequency-independent mounts. Given spectral variance in the mount properties, a simple roll mode decoupling scheme is suggested for the powertrain isolation system. Finally, an axiom for torque roll axis decoupling is provided by employing direct and adjoint eigenvalue problems.
On Anstreicher's combined phase I–phase II projective algorithm for linear programming

Anstreicher has proposed a variant of Karmarkar's projective algorithm that handles standard-form linear programming problems nicely. We suggest modifications to his method that we suspect will lead to better search directions and a more useful algorithm. Much of the analysis depends on a two-constraint linear programming problem that is a relaxation of the scaled original problem.
Fractal Networks of Inter‐Granular Voids in Pressed TATB

Small-angle neutron scattering techniques were used to study the evolution of void morphology with press- ed density of the insensitive high explosive, TATB. Samples were studied as a loose powder and as pressed pellets, ranging in density from approx. 1 to 1.804 g cm � 3 . Inter- granular voids in the loose powder were randomly ar- ranged (non-fractal) and had a surface defined mean size of 0.66 mm. Pressing was found to induce a fractal network of voids with fractally rough interfaces. The surface-defined mean void size of the pressed samples was between 0.21- 0.33 mm over the range of densities studied and was found to increase with pressed density up to 1.720 g cm � 3 ,d e- creasing thereafter. The volume fractal dimension, indica- tive of the void arrangement, mirrored the changes in the mean void size. No systematic change in the surface fractal dimension was found. Surface area analysis allowed the average TATB grain size within the pressed samples to be quantified. An initial decrease of the mean grain size fol- lowed by an increase with pressed density suggests that the TATB grains behave in a brittle fashion at low densities and ductile at higher pressed densities.
Kinetic Destabilization through Single Point Mutations Emphasizes the Critical Role Played by Coupled Tertiary Interactions in the Folding of the Azoarcus Ribozyme

Tertiary interactions stabilize RNA structure and impart function to RNAs. Using the Azoarcus group I ribozyme as a model system we determine the contributions of these interactions to folding of RNAs in general. Previous studies have taken a detailed thermodynamic look at key tertiary interactions for this ribozyme [1]. Here we make an effort to unravel the kinetic contributions of these tertiary interactions by abolishing them through single point mutations and studying the resulting dynamics through smFRET. We see that tertiary interaction mutants promote an increased number of excursions from the compact folded state of the ribozyme along with broadening the FRET population distribution. Our results show that the change in folding kinetics for each of the mutants is context dependent, providing us a kinetic stability map of the ribozyme's key tertiary interactions. A mutation in the P9 tetraloop results in the most “floppy” ribozyme, while a mutation in the P2 tetraloop causes only a small increase in transient unfolding, compared to the wild type ribozyme. Among the mutants, the folding rates show a smaller variation and are faster than the unfolding rates. These results show us how this long noncoding RNA has evolved to reduce conformational fluctuations as it proceeds in its folding path towards the native state.[1] Behrouzi R., Roh J.H., Kilburn D., Briber R.M., Woodson S.A.; Cell, 2012, 149, 2, 348-357
Choice of Residential Environment in the Randstad

This contribution adds to our earlier work on the residential choices of households who move, by studying the role of the residential environment in the relocation process. This is done by analysing individual household flows within and between residential environments. When residential environment is introduced, it aids the understanding of choices of tenure and type of dwelling. When residential environment is added as a characteristic of the choice set, we are able to show the way in which environment acts as a context for households' choices. Households choose almost uniformly to relocate within residential environments that are the same as those in which they originate, but the transitions between dwelling types (owning, single-family renting and multi-family renting) are most revealing of the relative roles of context (environment) and household composition. In particular, as in other Western countries, there is a sustained transfer to suburban environments, but mostly for family households.
Numerical Simulations of an Ultrasimple Ultrashort-Laser-Pulse Measurement Device-GRENOUILLE

We numerically simulate the performance of the grating-eliminated no-nonsence observation of ultrafast incident laser light E-fields (GRENOUILLE) device, an experimentally very simple variation of frequency-resolved optical gating (FROG) for measuring ultrashort laser pulses. GRENOUILLE has many subtleties because it uses the second-order nonlinearities of a thick nonlinear-optical crystal with relatively tightly focused and broadband pulses, in which the phase-matching bandwidth is deliberately made narrow compared to the pulse bandwidth. In the current study, we compute the nonlinear-optical signal field in the frequency domain and considered all sum-frequency-generation processes, both collinear and noncollinear. We compute the GRENOUILLE trace for practical examples and show that accurate measurements are easily obtained for properly designed devices
Farnesyltransferase Inhibitors: Preclinical Development

: The Ras proteins are low molecular weight GTP binding proteins that function in the regulation of the transduction of growth proliferative signals from the membrane to the nucleus. Oncogenically mutated ras genes are found in approximately 25% of all human cancers. Localization of the Ras oncoproteins to the inner surface of the plasma membrane is essential for their biological activity. This observation suggested that the enzyme that mediates the membrane localization, farnesyl-protein transferase (FPTase), would be a target for the development of novel anticancer agents. We have developed potent, cell-active inhibitors of FPTase that exhibit antiproliferative activity in cell culture and block the morphologic alterations associated with Ras-induced transformation of mammalian cells in monolayer cultures. In vivo, these compounds block the growth of ras-transformed fibroblasts in a nude mouse xenograft model and block the growth and, in some cases, cause regression of mammary and salivary tumors in several strains of ras transgenic mice in the absence of any detectable side effects. The results of our preclinical studies and those of others suggest that FTIs may have utility against a variety of human cancers, a hypothesis that is curently being tested in the clinic.
Minimum viable population and reserve sizes for naturally regulated grizzly bears in British Columbia

Abstract Estimating minimum viable population and reserve size is a fundamental cornerstone of conservation biology—but these estimates require representative demographic parameters. For example, “Benchmark” Grizzly Bear (Ursus arctos) Management Units in British Columbia (BC) are defined as unhunted and naturally regulated populations that can serve as population sources to surrounding hunted areas and provide information on natural population processes. Such benchmarks should have a very small probability of becoming threatened (N 1 2 K, 3 4 K, and K. Results indicated that 200–250 bears were required for a sufficiently small probability (P 20 years. Reserve sizes varied from 8556 km2 to 17,843 km2 depending on population density in each benchmark. These minimum viable populations and reserve sizes would protect approximately 12% of the estimated provincial grizzly bear population and would cover approximately 5% of the landmass of BC.
Recent results on the mechanism of earthquakes with implications for the prediction and control program

Abstract The problem of earthquake control was considered within the framework of the dislocation theory of earthquake faulting. Rupture velocity, rise time, and the shape of the fault control the efficiency of seismic energy radiation. An example of an inefficient earthquake due to its long, narrow shape is the Parkfield earthquake of 1966. The most serious bottleneck of all the research programs on earthquake prediction and control is how to measure the tectonic stress over a large volume of the earth's crust. Our attempt in the last few years to make such measurements using SH waves from underground explosions with yield ranging from less than 1/2 ton up to 1 megaton is described.