cssi/SciSciGPT-SciSciNet huggingface dataset:
Antibodies Elicited by an NS1-Based Vaccine Protect Mice against Zika Virus.

ABSTRACT Zika virus is a mosquito-borne flavivirus which can cause severe disease in humans, including microcephaly and other congenital malformations in newborns and Guillain-Barre syndrome in adults. There are currently no approved prophylactics or therapeutics for Zika virus; the development of a safe and effective vaccine is an urgent priority. Preclinical studies suggest that the envelope glycoprotein can elicit potently neutralizing antibodies. However, such antibodies are implicated in the phenomenon of antibody-dependent enhancement of disease. We have previously shown that monoclonal antibodies targeting the Zika virus nonstructural NS1 protein are protective without inducing antibody-dependent enhancement of disease. Here, we investigated whether the NS1 protein itself is a viable vaccine target. Wild-type mice were vaccinated with an NS1-expressing DNA plasmid followed by two adjuvanted protein boosters, which elicited high antibody titers. Passive transfer of the immune sera was able to significantly protect STAT2 knockout mice against lethal challenge by Zika virus. In addition, long-lasting NS1-specific IgG responses were detected in serum samples from patients in either the acute or the convalescent phase of Zika virus infection. These NS1-specific antibodies were able to functionally engage Fcγ receptors. In contrast, envelope-specific antibodies did not activate Fc-mediated effector functions on infected cells. Our data suggest that the Zika virus NS1 protein, which is expressed on infected cells, is critical for Fc-dependent cell-mediated immunity. The present study demonstrates that the Zika virus NS1 protein is highly immunogenic and can elicit protective antibodies, underscoring its potential for an effective Zika virus vaccine. IMPORTANCE Zika virus is a global public health threat that causes microcephaly and congenital malformations in newborns and Guillain-Barre syndrome in adults. Currently, no vaccines or treatments are available. While antibodies targeting the envelope glycoprotein can neutralize virus, they carry the risk of antibody-dependent enhancement of disease (ADE). In contrast, antibodies generated against the NS1 protein can be protective without eliciting ADE. The present study demonstrates the effectiveness of an NS1-based vaccine in eliciting high titers of protective antibodies against Zika virus disease in a mouse model. Sera generated by this vaccine can elicit Fc-mediated effector functions against Zika virus-infected cells. Lastly, we provide human data suggesting that the antibody response against the Zika virus NS1 protein is long-lasting and functionally active. Overall, our work will inform the development of a safe and effective Zika virus vaccine.
Non-periodic phase-space trajectories of roughness-driven secondary flows in high- boundary layers and channels

Turbulent flows respond to bounding walls with a predominant spanwise heterogeneity – that is, a heterogeneity parallel to the prevailing transport direction – with formation of Reynolds-averaged turbulent secondary flows. Prior experimental and numerical work has determined that these secondary rolls occur in a variety of arrangements, contingent only upon the existence of a spanwise heterogeneity (i.e. from complex, multiscale roughness with a predominant spanwise heterogeneity, to canonical step changes, to different roughness elements). These secondary rolls are known to be a manifestation of Prandtl’s secondary flow of the second kind: driven and sustained by the existence of spatial heterogeneities in the Reynolds (turbulent) stresses, all of which vanish in the absence of spanwise heterogeneity. Herein, we show results from a suite of large-eddy simulations and complementary experimental measurements of flow over spanwise-heterogeneous surfaces. Although the resultant secondary cell location is clearly correlated with the surface characteristics, which ultimately dictates the Reynolds-averaged flow patterns, we show the potential for instantaneous sign reversals in the rotational sense of the secondary cells. This is accomplished with probability density functions and conditional sampling. In order to address this further, a base flow representing the streamwise rolls is introduced. The base flow intensity – based on a leading-order Galerkin projection – is allowed to vary in time through the introduction of time-dependent parameters. Upon substitution of the base flow into the streamwise momentum and streamwise vorticity transport equations, and via use of a vortex forcing model, we are able to assess the phase-space evolution (orbit) of the resulting system of ordinary differential equations. The system resembles the Lorenz system, but the forcing conditions differ intrinsically. Nevertheless, the system reveals that chaotic, non-periodic trajectories are possible for sufficient inertial conditions. Poincare projection is used to assess the conditions needed for chaos, and to estimate the fractal dimension of the attractor. Its simplicity notwithstanding, the propensity for chaotic, non-periodic trajectories in the base flow model suggests similar dynamics is responsible for the large-scale reversals observed in the numerical and experimental datasets.
Wrangling Rogues: A Case Study on Managing Experimental Post-Moore Architectures

The Rogues Gallery is a new experimental testbed that is focused on tackling rogue architectures for the post-Moore era of computing. While some of these devices have roots in the embedded and high-performance computing spaces, managing current and emerging technologies provides a challenge for system administration that are not always foreseen in traditional data center environments.We present an overview of the motivations and design of the initial Rogues Gallery testbed and cover some of the unique challenges that we have seen and foresee with upcoming hardware prototypes for future post-Moore research. Specifically, we cover networking, identity management, scheduling of resources, and tools and sensor access aspects of the Rogues Gallery along with techniques we have developed to manage these new platforms. We argue that current tools like the Slurm scheduler can support new rogues without major infrastructure changes.
Immune checkpoint inhibition alters the inflammatory cell composition of human coronary artery atherosclerosis

Abstract Background Immune checkpoint inhibition (ICI) has emerged as a promising new approach to treat malignancy. Such therapies can result in autoimmune-related complications such as myocarditis and hepatitis. The impact of ICI on sites of preexisting chronic inflammation has been less clear. Atherosclerosis is a chronic vascular disease with a significant inflammatory component. Methods To determine the effect of ICI on the inflammatory infiltrate in coronary artery atherosclerotic plaques, 11 patients who had recently been treated with ICI and subsequently underwent autopsy were matched with 11 cancer patients who had not received ICI treatment. The amount of CD3+ T-lymphocytes, CD8+ cytotoxic T-lymphocytes, and CD68+ macrophages and the ratios of the various cell types in the coronary artery atherosclerotic plaques were compared. Results There was no significant difference in the absolute numbers of CD3+, CD8+, or CD68+ cells in the atherosclerotic plaques. In the plaques of the ICI-treated patients, there was a significant increase in the ratio of CD3+ cells to CD68+ cells (CD3/CD68) (P=.002) and a trend towards an increased CD8/CD68 ratio. The increased CD3/CD68 ratio in the ICI-treated patients resulted in 6 of the 11 patients having lymphocyte-predominate inflammation in contrast to the macrophage-predominate inflammation typically found in atherosclerotic plaques. Conclusions These findings indicate that ICI alters the inflammatory composition of human atherosclerotic plaque and, thus, may influence plaque progression and/or clinical coronary events. Summary In cancer patients, treatment with immune checkpoint inhibition is associated with an altered inflammatory cell composition in coronary artery atherosclerotic plaques with an increased ratio of CD3+ T cells to CD68+ macrophages. Thus, immune checkpoint inhibition may influence plaque progression and/or clinical coronary events.
Evaluation of pulmonary hypertension and surgical therapeutic effects using radionuclide pulmonary perfusion imaging in patients with pulmonary hypertension of valvular heart disease

Objective To evaluate pulmonary hypertension(PH) and surgical therapeutic effects using radionuclide pulmonary perfusion imaging in patients of valvular heart disease. Methods And material 115 patients accumulated with valvular disease were included from May 2001 to August 2007. Echocardiography and first-pass radionuclide pulmonary perfusion imaging(FPPPI) were performed in all patients before surgery,7days after surgery and 3 months after surgery(33cases). Patients were divided into four groups. Pulmonary artery pressure (PAP) is normal group[mean pulmonary arterial pressure (MPAP)≤20mm Hg(1 mm Hg =0. 133 kPa)]; PAP slightly rise group[20 mm Hg 50 mm Hg]. Results Lung Equilibrium Time (LET)by FPPPI were(18.87 ± 4.80) s, (26. 17 ± 7.09) s, (38.48 ± 7.09) s and (54.59 ± 7.96) s in this four groups before surgery. LET were 17.58 ±4.52, 21.51 ±6.44, 23.94 ±5.85, 27.29 ±6.70 in this four groups 7 days after surgery (P<0.001). There were no siguificantly differences of LET in 33 cases 3 months after surgery compared with those of 7 days after surgery. Conclusion Pulmonary arterial pressure siguificantly decreased 7 days after surgery in patients with PH of valvular heart disease, especially in those of slightly and moderate rise groups. FPPPI is an accuracy method in evaluating surgical therapeutic effects in valvular heart disease. Key words: Heart valve diseases; Angiocardiography; Isotope labeling; Pulmonary hypertension; Radionuclide pulmonary perfursion imaging
European Registry on Helicobacter pylori management shows that gastroenterology has largely failed in its efforts to guide practitioners

The authors report the results of a 5-year (2013–2018) audit of the effectiveness of Helicobacter pylori therapy in clinical practice in several regions of Europe.1 The study provides a contemporary prospective regarding empirical H. pylori treatment. Importantly, there was little centralised influence on choice of therapy apart from sending periodic updates, presenting updates at the meeting of the European H. pylori study group and including local feedback in the form of post-treatment testing for cure. The strengths of the report include the large sample size, representative population, and high level of complete data on treatment type, duration and follow-up. Overall, 30 394 patients from 27 European countries provided data on 21 533 first-line empirical H. pylori treatments using more than 100 different schemes. Antibiotic susceptibility data were obtained from 11% (2.7% to 16.7% in different regions). In that small sample, the prevalence of H. pylori resistance to clarithromycin and metronidazole was high (ie, 23% and 32%, respectively). Clarithromycin triple therapy was most commonly used but use declined over time from >50% in 2013–2015 to 32% in 2017–2018. The use of bismuth quadruple therapy was uncommon and varied markedly between regions but also tended to increase over time. They concluded that the management of H. pylori infection by European gastroenterologists was heterogeneous, suboptimal and discrepant with current recommendations. There seems to be an ongoing slow paradigm shift from therapies identified by trial and …
Approach to Microscopic Hematuria

Microscopic hematuria is common incidental discovery on urinalysis. This teaching scripts leads the reader through a systematic approach to this problem. We emphasize the importance of discerning patient symptoms that might point towards an etiology, and the distinction between “glomerular” and “nonglomerular” etiologies.
GPCR Signaling in Ca2+ Homeostasis: The PTH Type 1 and Calcium-Sensing Receptors

Abstract The parathyroid hormone (PTH) type 1 receptor (PTHR) is a medically important class B G Protein Coupled Receptor (GPCR) that primarily couples to Gs/cAMP and Gq/Ca2 + signaling pathways and has a central role in regulating Ca2 + homeostasis and bone turnover via PTH. Over the last decade, new molecular mechanisms of PTHR signaling and regulation of PTH secretion via the calcium-sensing receptor (CaSR) have emerged for a comprehensive understanding of how PTH/PTHR system functions. This chapter discusses these mechanisms and their physiological and disease relevance.
Barriers to Inquiry-Based Instruction: A Longitudinal Study of History Teachers:

While there has been an increased focus on inquiry-based learning in teacher preparation programs, little is known about the influences of these programs on teacher development over time. Using act...
Connectivity profile laterality in corticostriatal functional circuitry: a fingerprinting approach

An abnormal magnitude of hemispheric difference (i.e. laterality) in corticostriatal circuits is a shared feature of numerous neurodevelopmental and psychiatric disorders. Detailed quantitation and regional localization of corticostriatal laterality in normative samples stands to further the understanding of hemispheric differences in healthy and disease states. Here, we used a fingerprinting approach to quantify "functional connectivity profile laterality" - the overall magnitude by which a voxels profile of connectivity with homotopic regions of the ipsilateral and contralateral cortex differs - in the striatum. Laterality magnitude heatmaps revealed "laterality hotspots" - constituting outliers in the voxel-wise distribution -in the right ventrolateral putamen and left central caudate. Findings were replicated in an independent sample, with significant (p<0.05) spatial overlap observed between the location of the laterality hotspots across samples, as measured via Dice coefficients. At both hotspots, a primary driver of overall laterality was the difference in striatal connectivity strength with the right and left pars opercularis of the inferior frontal gyrus. Right and left striatum laterality magnitude maps were found to significantly differ (p<0.05) at the hotspot locations. Moreover, using subjects left, but not right, striatum laterality magnitude maps, a support vector machine trained on a discovery sample (n=77) and tested on a replication sample (n=77) significantly predicted (r=0.25, p=0.028) subject performance on a language task, known for its lateralized nature. Laterality magnitude maps remained consistent across different cortical atlas parcellations and did not differ significantly between right-handed and left-handed individuals. In sum, meaningful variation in functional connectivity profile laterality - both spatially within the striatum and across subjects - is evident in corticostriatal circuits. Findings provide a basis to examine corticostriatal connectivity profile laterality in psychiatric illness.
Population-based Incidence and Outcomes of Compressive Optic Neuropathy

Abstract Purpose Prior studies on compressive optic neuropathy (CON) have come from large tertiary centers, which may contain referral bias toward more severe or atypical disease. To our knowledge, there are no studies to determine the population-based etiologies and clinical outcomes of compressive optic neuropathy (CON). This study aims to bridge that gap using the Rochester Epidemiology Project database. Design Retrospective, population-based cohort Methods Medical records of all residents living in Olmsted County, Minnesota from January 1, 2000 through December 31, 2018 were screened for CON. Demographic and clinical information were collected before and after treatment. Results 23 patients had a confirmed diagnosis of CON during our study period, which provided an overall incidence of 1.14 per 100,000 per year. Average age at onset of CON was 51 years (SD 24), and 39% were male. The most common etiologies were pituitary adenoma and meningioma. There was significant improvement in visual fields (p Conclusion To our knowledge, this study provides the first population-based incidence of CON. The finding that earlier treatment leads to better visual outcomes stresses the importance of having CON on the differential diagnosis of patients with optic neuropathy.
The Future of Digital Human Rights

The final chapter of the book discusses the implications of the book’s findings for social science. Several future concerns emerge. For the European Union to continue supranational data management and technology governance, it must address feelings of democratic deficit among EU citizens. Second, as many EU states continue to suffer from terror attacks, state authorities increasingly rely upon data surveillance to forego risk, threatening the provision of digital human rights. Furthermore, exogeneous shocks such as the Covid-19 pandemic have caused governments to utilize personal data monitoring to manage public health, again crossing boundaries set by data protection legislation. Though the EU has shown itself willing to hold third parties responsible for protecting EU citizens’ data, states like China and the US, and data brokers, are increasingly pushing back against the EU view of digital human rights. As with all human rights, digital human rights are fragile.
Applied Problems of Radon Transform

Time series analysis and Grassmannians by V. M. Buchstaber Inversion of the generalized Radon transform by A. S. Denisyuk Generalized projection and section theorems in diffraction tomography by A. N. Panchenko Computation of singular convolutions by D. A. Popov and D. V. Sushko Mathematical models in two-dimensional Radon tomography by D. A. Popov, E. B. Sokolova, and D. V. Sushko Mathematical aspects of polarization tomography by V. A. Sharafutdinov Exponential Radon transform by I. Ya. Shneiberg On a new reconstruction algorithm in emission tomography by I. Ya. Shneiberg, I. V. Ponomarev, V. A. Dmitrichenko, and S. D. Kalashnikov Examples of nonuniquenss in problems related to the generalized Radon transform and emission tomography with absorption by L. Vertgeim.
Application of molecular genetics to the study of microbial communities

The character of studies of microbial mats is being changed by the use of molecular genetic techniques. Since these techniques are not dependent upon the vagaries of enrichment and pure culture isolation, they promise a complete accounting of commumty structure and direct access to the study of microorganisms at the levels of populations and single cells. Thus, the integration of molecular techniques with more standard techniques (e.g. microscopy, microelectrodes, stable isotopes, radiotracers, and analytical chemistry) should prove a powerful synthesis. Our goal is not to provide a review of all the recent literature (and we apologize for any omissions in this regard) but rather to provide perspective on available and developing techniques.
Manifold reconstruction from unorganized points

A new algorithm for manifold reconstruction is presented. The goal is to take samples drawn from a finite dimensional manifold, and to reconstruct a manifold, based only on the samples, which is a good approximation to the true manifold; nothing of the true manifold's geometry or topology is known a priori. The algorithm constructs a simplicial complex based on approximating tangent hyperplanes to the manifold, and does so efficiently. Successful examples are presented for curve reconstruction in the plane, curve reconstruction in space, and surface reconstruction in space.
Entrevista a Ricardo Tacuchian

O prof. Kwabena Nketia, apos seus estudos fundamentais em Gana, transferiu-se, em 1944, para Londres, onde estudou Linguistica e Musica Ocidental (isto e, teoria, musicologia e piano). Em 1949 retomou para sua terra natal onde assumiu uma posicao de pesquisador de Musica Africana, na Universidade de Gana, durante dez anos. Em 1958 recebeu uma bolsa da Rockfeller Foundation e foi estudar na Julliard School of Music, tendo entre outros professores, o compositor Henry Cowell. Em 1968, Nketia assumiu uma posicao na UCLA. Em 1982, transfere-se de Los Angeles para a University of Pittsburgh onde trabalha ate hoje. A atividade academica do pesquisador, nos Estados Unidos, alternou-se com as atividades no lnstitute of African Studies da University of Ghana.
Isoprenylation of a protein kinase. Requirement of farnesylation/alpha-carboxyl methylation for full enzymatic activity of rhodopsin kinase.

The primary structure of bovine rhodopsin kinase (RK), which phosphorylates light-activated rhodopsin (Rho*), terminates with the amino acid sequence Cys558-Val-Leu-Ser561, a motif that has been shown to direct the isoprenylation and alpha-carboxyl methylation of many proteins (e.g. p21Ha-ras). Transient expression of RK in COS-7 cells revealed the presence of two immunoreactive protein species. Consistent with RK being modified by isoprenylation, interconversion of these two species was dependent upon isoprenoid biosynthesis in the cells. Moreover, a serine substitution for Cys558 resulted in a single RK species whose migration on sodium dodecyl sulfate-polyacrylamide gels was identical to that of RK from cells treated with mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and, thus, of isoprenoid biosynthesis. This finding indicates that isoprenylation of RK requires Cys558. The electrophoretic mobility of isoprenylated RK synthesized in COS-7 cells was identical to that of RK from bovine rod outer segments, suggesting that RK is isoprenylated in vivo. RK was determined to be modified by a farnesyl moiety and alpha-carboxyl-methylated. A time course of Rho* phosphorylation revealed that non-processed RK is approximately 4-fold less active than wild-type RK. This is the first demonstration of isoprenylation/alpha-carboxyl methylation of a protein kinase, and suggests that these modifications markedly influence enzymatic activity in vivo.
Ubiquitous process engineering: applying software process technology to other domains

Software engineering has learned a great deal about how to create clear and precise process definitions, and how to use them to improve final software products. This paper suggests that this knowledge can also be applied to good effect in many other domains where effective application of process technology can lead to superior products and outcomes. The paper offers medical practice and government as two examples of such domains, and indicates how process technology, first developed for application to software development, is being applied with notable success in those areas of endeavor. The paper also notes that some characteristics of these domains are highlighting ways in which current process technology seems to be inadequate, thereby suggesting ways in which this research is adding to the agenda for research in software process.
The macrophage-derived proteins murine RELMα and human resistin regulate host immunity to helminth infection (MPF3P.801)

Th2 cells are essential for protective immunity to helminths but also contribute to chronic inflammation. Here we identify the REsistin-Like Molecules RELMα and Resistin as critical mediators of this balance between helminth Th2-mediated immunity and inflammation in both murine infection and human studies. Following infection with Nippostrongylus brasiliensis, we observed significant macrophage expression of RELMα in the lungs. When RELMα-/- mice were infected with N. brasiliensis, there were increased Th2-type responses, accelerated worm expulsion and exacerbated lung inflammation compared to wild-type mice, implicating a role for RELMα in dampening Th2 immune responses. Selective depletion of macrophages in RELMα-/- mice ameliorated N. brasiliensis-induced chronic lung inflammation, suggesting that RELMα modulates inflammation through effects on macrophages. In new translational studies, we investigated the function of human Resistin (hResistin) which shares sequence homology with RELMα. Employing transgenic mice that express hResistin, we observed increased macrophage expression of hResistin in N. brasiliensis-infected lungs. Moreover, hResistin inhibited Th2 immune responses and immunity to N. brasiliensis. Finally, we observed a strong correlation between parasite number and serum Resistin levels in a population of helminth-infected patients (n=46). Taken together, these studies identify a new RELM-mediated regulatory pathway in helminth immunity and inflammation.
Erythroid Cell Differentiation and the Synthesis and Assembly of Hemoglobin

Publisher Summary This chapter focuses on erythroid cell differentiation and the synthesis and assembly of hemoglobin. The control of hemoglobin synthesis is concerned with the following: (1) the determination of the primary structure of each chain, (2) differentiation of erythroid cells and the induction of hemoglobin synthesis, (3) the switch from the synthesis of embryonic to fetal hemoglobin and of fetal to adult hemoglobin during gestation and early postnatal life, (4) the coordination of synthesis of alpha chains and of their complementary beta, gamma, delta, and epsilon chains, and (5) the regulation and coordination of the syntheses of heme and of globin. The sensitivity of hemoglobin synthesis to 5-fluorouracil and to bromodeoxyuridine only up to the head process stage suggests that DNA synthesis is necessary for hemoglobin synthesis only during these early stages. The differentiation of erythroid cells, the induction of hemoglobin synthesis, and the switch from embryonic and fetal to adult hemoglobin synthesis may be explicable in terms of control at the level of transcription of genes. The mechanism of action of heme in promoting the formation of polyribosomes, accelerating the synthesis of globin, and regulating the assembly of hemoglobin is under study. The synthesis of heme is controlled by feedback inhibition of the formation of ALA. Heme stimulates the synthesis of globin and promotes the coordinate assembly of hemoglobin. This schema of regulation is helpful in understanding the induction and control of hemoglobin synthesis in developing erythroid cells, and it provides a framework for clarifying various disorders of hemoglobin metabolism in man.
Donor-specific antibody to trans-encoded donor HLA-DQ heterodimer

The majority of de novo donor specific HLA antibodies (DSAs) in transplant patients are directed to HLA-DQ antigens, which consist of a heterodimer of alpha and beta chains. Although a heterodimer can theoretically be cis- or trans-encoded, the sensitizing forms generally appear to be forms. DSA to DQ trans-heterodimer has never been reported. We reviewed 360 post-kidney transplant recipients (transplant: 2002-2013; follow-up: 5.6±3.3years). DQ DSA was detected in 46 of 57 patients who developed DSA. DSA specificity was consistent with donor mismatched DQ trans-heterodimers in three patients: DQ2.5 (DQB1*02, DQA1*05), DQ2.3 (DQB1*02, DQA1*03), and DQ4.3 (DQB1*04, DQA1*03). Two of them eventually lost grafts (2 and 5years later) with allograft nephropathy. In conclusion, post-transplant patients may develop DSA to donor DQ trans-heterodimers. Further studies are warranted to determine the clinical significance of such DSAs.
Fluorescent Cell Barcoding for Multiplex Flow Cytometry

Fluorescent cell barcoding (FCB) enables high throughput, high content flow cytometry by multiplexing samples prior to staining and acquisition on the cytometer. Individual cell samples are barcoded, or labeled, with unique signatures of fluorescent dyes so that they can be mixed together, stained, and analyzed as a single sample. By mixing samples prior to staining, antibody consumption is typically reduced 10- to 100-fold. In addition, data robustness is increased through the combination of control and treated samples, which minimizes pipetting error, staining variation, and the need for normalization. Finally, speed of acquisition is enhanced, enabling large profiling experiments to be run with standard cytometer hardware. In this unit, we outline the steps necessary to apply the FCB method to cell lines, as well as primary peripheral blood samples. Important technical considerations, such as choice of barcoding dyes, concentrations, labeling buffers, compensation, and software analysis, are discussed.
Disorder guides protein function

Cellular function requires biomolecules to undergo dynamic transitions that include folding, conformational rearrangements, and large-scale assembly. The result is a highly interdependent network of processes that is maintained by a balance of thermodynamic and kinetic factors. In molecular machines, each constituent biopolymer (i.e., a chain of residues) first folds to a low-energy configuration/ensemble. These ordered polymers can then assemble into sophisticated architectures, which undergo conformational transitions during function. In contrast to the dynamics of macroscopic machines, molecular-level processes are stochastic, where the molecular interactions that ensure structural integrity are weak (i.e., on the scale of energetic fluctuations from solvent). In this dynamic environment, biomolecules constantly fluctuate (1), and the extent of disorder is heterogeneous between residues. Inspired by this, in 2003, Miyashita et al. postulated that biomolecules may exploit disorder to accelerate functional kinetics (2). In their theoretical investigation of protein function, the authors found large levels of strain energy accumulate in isolated residues. The predicted level of strain exceeded the stability of most proteins under cellular conditions, suggesting that these highly-strained regions may locally unfold, or “crack.” By cracking, the molecule may gain configurational entropy and thereby reduce the strain-induced barrier (Fig. 1). Subsequently, many theoretical and computational investigations have found evidence of cracking during function. These studies have primarily used simplified models (3), with which millisecond-scale dynamics are computationally accessible. In contrast, simulations with explicit-solvent models are typically limited to nanoseconds, or occasionally microseconds (4, 5). Because cracking and large-scale rearrangements occur on relatively long timescales (microseconds to milliseconds), evidence of cracking with explicit-solvent models has been sparse. In PNAS, Shan et al. (6) report the most definitive evidence of cracking from explicit-solvent simulations, to date. Using a specialized computer, they performed multiple simulations of EGFR kinase in solvent for tens of microseconds and found cracking to spontaneously occur. Although open questions remain about the precise details of cracking properties, Shan et al.’s study highlights how convergent theoretical descriptions of biological dynamics are emerging as explicit-solvent simulations are pushed to longer timescales.
Improving the Sensitivity of Health Professionals to the Needs of Patients and Families: An Experiment.

This study examines, by means of a quasi-experimental design, the impact of a variety of methods involving humanistic, didactic, and experiential modalities in training students—potential health professionals—in empathy-sensitivity and interpersonal skills. An eclectic, multimodal approach using audiovisual technology, role playing, observation, and discussion was found to be most effective in raising levels of sensitivity.
Effect of meclofenamate or ketoconazole on the natriuretic response to increased pressure.

Increases in renal interstitial hydrostatic pressure (RIHP) by direct renal interstitial volume expansion (DRIVE) decrease proximal sodium reabsorption and increase urinary fractional sodium excretion (FENa). This natriuretic response is blunted by inhibition of the cyclooxygenase pathway. However, complicating the interpretation of the effects of cyclooxygenase inhibition on sodium excretion are the following: (1) products of the other pathways of arachidonic acid metabolism, such as the cytochrome P-450 metabolites, may be attenuated when cyclooxygenase activity is reduced; (2) the proximal tubule has a high biosynthetic capacity for cytochrome P-450 metabolites of arachidonic acid. Therefore, the purpose of the present study was to compare blockade of the epoxygenase products of the cytochrome P-450 pathway with ketoconazole to blockade of the cyclooxygenase pathway with meclofenamate on the natriuretic response to increased RIHP during DRIVE. RIHP, fractional excretion of lithium (FELi), FENa, and glomerular filtration rate (GFR) were measured before and after DRIVE in control (n = 6), meclofenamate-treated (n = 6), and ketoconazole-treated (n = 5) rats. DRIVE was achieved by infusing 100 μI of 2.5% albumin solution directly into the renal interstitium. In control animals, DRIVE significantly increased RIHP (Δ2.8 ± 0.6 mm Hg), FELI (Δ13.4% ± 5.2%), and FENa (Δ1.29% ± 0.31%). In the ketoconazole-treated group, RIHP (Δ3.9 ± 0.8 mm Hg), FELi (Δ19.3% ± 2.0%), and FENa (Δ1.73% ± 0.43%) also significantly increased. However, the natriuretic response to DRIVE was blunted during cyclooxygenase blockade with meclofenamate when compared with control or ketoconazoletreated animals (FELi (Δ2.5% ± 1.4%, not significant) and FENa (Δ0.07% ± 0.18%, not significant)), even though the response of RIHP was intact (Δ4.5 ± 0.4 mm Hg, p < 0.001). These results suggest that the natriuretic response to increased RIHP is dependent on the presence of, but not necessarily the increased synthesis of, products of cyclooxygenase rather than the cytochrome P-450 epoxygenase pathway for arachidonic acid metabolism.
A School-Based Health Education Program Can Improve Cholesterol Values for Middle School Students

This prospective study aimed to measure the impact of a school-based multidisciplinary education program on risk factors for atherosclerosis in sixth-grade students. A prospective study was performed in which patients served as their own controls. Healthy sixth-grade students from three middle schools in a city of approximately 100,000 were exposed to an educational program promoting healthful habits through behavioral and environmental change. Risk factors including body mass index (BMI), systolic and diastolic blood pressure (SBP and DBP), cholesterol panel, and random blood glucose were measured before program initiation, then 5 months afterward. Of 711 sixth-graders at three middle schools, 287 (47% boys; mean age, 11.5 ± 0.37 years) consented to participate in the study. The mean total cholesterol value decreased from 169 ± 26 to 154 ± 26 mg/dl (p < 0.0001). The low-density lipoprotein (LDL) cholesterol value decreased from 86 ± 25 to 84 ± 23 mg/dl (p = 0.01), and the high-density lipoprotein (HDL) cholesterol value decreased from 56 ± 13 to 50 ± 13 mg/dl (p < 0.0001). The random glucose value decreased from 96 ± 13 to 93 ± 15 mm/dl (p = 0.01). The mean SBP did not change, showing 109 ± 12.5 mmHg before the program and 108 ± 11.5 mmHg afterward. The DBP decreased from 63.6 ± 8.6 to 62.3 ± 7.8 mmHg (p = 0.01). The Project Healthy Schools program is feasible and appears to be effective. The results showed significant improvement in risk factors for early atherosclerosis among sixth-grade students including total cholesterol, LDL cholesterol, random glucose levels, and diastolic blood pressure. Further study with a larger group and a longer follow-up period would be valuable.
Aneurysm of Saphenous Vein Graft of the Common Carotid Artery: A Case Report and Review of Literature

Aneurysmal failures occurring in vein grafts inserted into arterial systems generally occur relatively soon after placement. We describe, however, this rare complication in a saphenous vein graft to the common carotid artery 15 years postoperatively.
A comparison of methods for intermediate fine mapping

The arrival of highly dense genetic maps at low cost has geared the focus of linkage analysis studies toward developing methods for placing putative trait loci in narrow regions with high confidence. This shift has led to a new analytic scheme that expands the traditional two-stage protocol of preliminary genome scan followed by fine mapping through inserting a new stage in between the two. The goal of this new "intermediate" fine mapping stage is to isolate disease loci to narrow intervals with high confidence so that association studies can be more focused, efficient, and cost-effective. In this paper, we compared and contrasted five methods that can be used for performing this intermediate step. These methods are: the lod support approach, the generalized estimating equations (GEE) method, the confidence set inference (CSI) procedure, and two bootstrap methods. We compared these methods in terms of the coverage probability and precision of localization of the resulting intervals. Results from a simulation study considering several two-locus models demonstrated that the two bootstrap methods yield intervals with approximately correct coverage. On the other hand, the 1-lod support intervals, and those produced by the GEE method, tend to significantly undercover the trait locus, while the regions obtained by the CSI incline to overcover the gene position. When the observed coverage of the confidence intervals produced by all the methods was held to be the same, those obtained through the CSI procedure displayed a higher ability to localize loci, especially when these loci have a minor contribution to the trait and when the amount of data available for the analysis is relatively small. However, with very large sample sizes, lod support intervals emerged as a winner. Application of the methods to the data from the Arthritis Research Campaign National Repository led to intervals containing the position of a known trait locus for all methods, with the greatest precision achieved by the CSI.
Expression and purification of glycine N-methyltransferases in Escherichia coli ☆

Expression and purification of recombinant mouse, rat, and human glycine N-methyltransferases (GNMTs) in pTYB and pET expression vectors was done in order to prepare the proteins for structure studies of the enzymes from different sources. When human and mouse GNMTs were expressed in pTYB vector as a fusion protein with intein and the chitin binding domain, an unusual cleavage of intein was found. This cleavage takes place at two sites near the N-terminus of intein. This resulted in the appearance of an abnormal GNMT protein after on-column cleavage of the fusion protein, which could not be separated from normal GNMT. For this reason expression of mouse, rat, and human GNMTs was done in the pET-17b expression vector, resulting in the expression of soluble protein at about 20-40mg/L of culture. A new procedure for GNMT isolation after expression in the pET vector was developed. This included only two steps, ammonium sulfate precipitation and ion-exchange chromatography, and resulted in preparations containing 95-97% pure protein. All expressed proteins were tetrameric with molecular weights of 130kDa as determined by size-exclusion chromatography. Activity in Tris buffer at pH 9 of mouse, rat, and human GNMTs was found to be 255, 260, and 540U/mg, respectively. This implies that expressed and purified GNMT proteins are biologically active and suitable for biochemical and structural studies.
The human side of service engineering

Service engineering is concerned with applying engineering methods to make and scale diverse types of service systems, which range from transportation and finance to health care and government. What makes modern service engineering uniquely challenging is the need not only to consider the technical side of these system designs but also to focus on how these systems engage, relate to, and are perceived to contribute to the self-actualization goals of their all-too-human “cocreators of value.” Service systems must have a wide-ranging “human side.” In this article, we propose a framework to scope and better define the human side of modern service systems. We then explore how to impact the cocreation of value in modern service systems, characterized by their digital, interconnected, dynamic, and human-intensive nature. In conclusion, we relate the other articles in this special issue to this modern service system framework, as well as suggesting future research directions. © 2012 Wiley Periodicals, Inc. © 2013 Wiley Periodicals, Inc.
Capacitive-Piezoelectric Transducers for High- $Q$ Micromechanical AlN Resonators

A capacitive-piezoelectric (also known as, capacitive-piezo) transducer that combines the strengths of capacitive and piezoelectric mechanisms to achieve a combination of electromechanical coupling and Q higher than otherwise attainable by either mechanism separately, has allowed demonstration of a 1.2-GHz contour-mode aluminum nitride (AlN) ring resonator with Q > 3000 on par with the highest measured d 31-transduced AlN-only piezoelectric resonators past 1 GHz, and a 50-MHz disk array with an even higher Q > 12 000. Here, the key innovation is to separate the piezoelectric resonator from its metal electrodes by tiny gaps to eliminate metal material and metal-to-piezoelectric interface losses thought to limit thin-film piezoelectric resonator Q , while also maintaining high electric field strength to preserve a strong piezoelectric effect. While Q increases, electromechanical coupling decreases, but the k $^{2}_{\rm eff}{}\cdot {}$ Q product can still increase overall. More importantly, use of the capacitive-piezo transducer allows a designer to trade electromechanical coupling for Q , providing a very useful method to tailor Q and coupling for narrowband radio frequency (RF) channel-selecting filters for which Q trumps coupling. This capacitive-piezo transducer concept does not require dc-bias voltages and allows for much thicker electrodes that reduce series resistance without mass loading the resonant structure. The latter is especially important as resonators and their supports continue to scale toward even higher frequencies. [2013-0395]
Virtual-crystal approximation that works: Locating a compositional phase boundary in Pb(Zr 1-x Ti x )O 3

We present a method for modeling disordered solid solutions, based on the virtual crystal approximation (VCA). The VCA is a tractable way of studying configurationally disordered systems; traditionally, the potentials which represent atoms of two or more elements are averaged into a composite atomic potential. We have overcome significant shortcomings of the standard VCA by developing a potential which yields averaged atomic properties. We perform the VCA on a ferroelectric oxide, determining the energy differences between the high-temperature rhombohedral, low-temperature rhombohedral, and tetragonal phases of $\mathrm{Pb}({\mathrm{Zr}}_{1\ensuremath{-}x}{\mathrm{Ti}}_{x}){\mathrm{O}}_{3}$ at $x=0.5$ and comparing these results to superlattice calculations and experiment. We then use our method to determine the preferred structural phase at $x=0.4.$ We find that the low-temperature rhombohedral phase becomes the ground state at $x=0.4,$ in agreement with experimental findings.
Networking standards and russell's revisionism (review of, "Open standards and the digital age: history, ideology, and networks, russel, a.; 2014)[book review]

This column discusses the evolution of networking standards, looking at the history of open standards and the evolution of the communities that designed the Internet, particularly in regards to Andrew Russell's book Open Standards and the Digital Age: History, Ideology, and Networks. In this book, the author weaves two scholarly stories into one—namely, the history of open standards and the evolution of the communities that designed the Internet. The first theme involves plenty of archival dust, tracing its roots to the American standards movement of the railway era and modern industrialization after World War I. The bulk of the second theme is a lot less dusty, covering events on both sides of the Atlantic in the 1960s, 70s, 80s, and early 90s. It gets into arguments that modern readers will find engaging. More to the point, the book offers a revision of the common understanding of TCP/IP’s origins and evolution. Russell seeks to punctuate many popular myths about the role of participatory democracy. The book is a bit dense with facts. Some readers may decide it takes a tad too long—306 pages—to get to the good stuff.
Keeping peace with the microbiome: acetate dampens inflammatory cytokine production in intestinal epithelial cells

Keeping peace with the microbiome: acetate dampens inflammatory cytokine production in intestinal epithelial cells
Mechanisms of Earth Fissuring Caused by Groundwater Withdrawal

Earth fissures associated with groundwater withdrawal are complex products of both human activities and natural forces, and they occur in definable geological environments. In this paper, the authors first characterize the driving forces for earth fissures caused by groundwater withdrawal. Then, the effects of various factors, such as stresses and pre-existing geological structures, are examined using conceptual models. Numerical results show that the fissuring process is controlled not only by the induced movement at depth and pre-existing structures but also by the in situ stress field. In addition, the degree to which aquifer movement and pre-existing structures actually trigger fissuring depends greatly on the in situ stress field. The authors conclude that earth fissuring related to groundwater withdrawal is a multi-step process that is influenced by a multiplicity of factors, one being the aquifer movement. With groundwater withdrawal, hydraulic and gravitational forces tend to drive aquifer material to deform both horizontally and vertically. Cumulative deformation or strain results in movement. In turn, this aquifer movement results in differential displacements at depth along planes of weakness, such as pre-existing faults and material interfaces. This differential movement (both horizontal and vertical) then generates tensile zones at depth. Once formed, such a tensile zone may migrate upward, form a crack (fail) where the vadose zone is brittle, and eventually express itself as an earth fissure at the land surface in arid or semi-arid regions. In humid regions, the same tensile zone (lateral stretching) at depth will simply express itself as a transient sub-vertical plane of enhanced porosity within and crossing the vadose zone.
A proposal for detecting second order topological quantum phase

Abstract Gaussian linking of a semiclassical path of a charged particle with a magnetic flux tube is responsible for the Aharonov–Bohm effect, where one observes interference proportional to the magnitude of the enclosed flux. We construct quantum mechanical wave functions where semiclassical paths can have second order linking to two magnetic flux tubes, and show there is interference proportional to the product of the two fluxes.
Borderline resectable pancreatic cancer: Definitions and management

Pancreatic cancer is the fourth leading cause of cancer death in the United States. While surgical resection remains the only curative option, more than 80% of patients present with unresectable disease. Unfortunately, even among those who undergo resection, the reported median survival is 15-23 mo, with a 5-year survival of approximately 20%. Disappointingly, over the past several decades, despite improvements in diagnostic imaging, surgical technique and chemotherapeutic options, only modest improvements in survival have been realized. Nevertheless, it remains clear that surgical resection is a prerequisite for achieving long-term survival and cure. There is now emerging consensus that a subgroup of patients, previously considered poor candidates for resection because of the relationship of their primary tumor to surrounding vasculature, may benefit from resection, particularly when preceded by neoadjuvant therapy. This stage of disease, termed borderline resectable pancreatic cancer, has become of increasing interest and is now the focus of a multi-institutional clinical trial. Here we outline the history, progress, current treatment recommendations, and future directions for research in borderline resectable pancreatic cancer.