cssi/SciSciGPT-SciSciNet huggingface dataset:
A Threading-Based Method for the Prediction of DNA-Binding Proteins with Application to the Human Genome

Diverse mechanisms for DNA-protein recognition have been elucidated in numerous atomic complex structures from various protein families. These structural data provide an invaluable knowledge base not only for understanding DNA-protein interactions, but also for developing specialized methods that predict the DNA-binding function from protein structure. While such methods are useful, a major limitation is that they require an experimental structure of the target as input. To overcome this obstacle, we develop a threading-based method, DNA-Binding-Domain-Threader (DBD-Threader), for the prediction of DNA-binding domains and associated DNA-binding protein residues. Our method, which uses a template library composed of DNA-protein complex structures, requires only the target protein's sequence. In our approach, fold similarity and DNA-binding propensity are employed as two functional discriminating properties. In benchmark tests on 179 DNA-binding and 3,797 non-DNA-binding proteins, using templates whose sequence identity is less than 30% to the target, DBD-Threader achieves a sensitivity/precision of 56%/86%. This performance is considerably better than the standard sequence comparison method PSI-BLAST and is comparable to DBD-Hunter, which requires an experimental structure as input. Moreover, for over 70% of predicted DNA-binding domains, the backbone Root Mean Square Deviations (RMSDs) of the top-ranked structural models are within 6.5 A of their experimental structures, with their associated DNA-binding sites identified at satisfactory accuracy. Additionally, DBD-Threader correctly assigned the SCOP superfamily for most predicted domains. To demonstrate that DBD-Threader is useful for automatic function annotation on a large-scale, DBD-Threader was applied to 18,631 protein sequences from the human genome; 1,654 proteins are predicted to have DNA-binding function. Comparison with existing Gene Ontology (GO) annotations suggests that approximately 30% of our predictions are new. Finally, we present some interesting predictions in detail. In particular, it is estimated that approximately 20% of classic zinc finger domains play a functional role not related to direct DNA-binding.
Notes on Patristic Philosophy

Three eminent scholars, Professors Robert M. Grant, T. A. Burkill, and Cyril C. Richardson, in their reviews of my Religious Philosophy, have raised certain problems touching on topics in Patristic philosophy. The problems are of such importance as to call for further consideration.
Nutrient loading by anadromous alewife (Alosa pseudoharengus): contemporary patterns and predictions for restoration efforts

Anadromous alewives (Alosa pseudoharengus) have the potential to alter the nutrient budgets of coastal lakes as they migrate into freshwater as adults and to sea as juveniles. Alewife runs are generally a source of nutrients to the freshwater lakes in which they spawn, but juveniles may export more nutrients than adults import in newly restored popu- lations. A healthy run of alewives in Connecticut imports substantial quantities of phosphorus; mortality of alewives con- tributes 0.68 g Pfish -1 , while surviving fish add 0.18 g P, 67% of which is excretion. Currently, alewives contribute 23% of the annual phosphorus load to Bride Lake, but this input was much greater historically, with larger runs of bigger fish contributing 2.5 times more phosphorus in the 1960s. A mesocosm experiment in a nearby lake showed that juvenile ale- wife growth is strongly density dependent, but early survival may be too low for juvenile outmigration to balance adult in- puts. In eutrophic systems where nutrients are a concern, managers can limit nutrient loading by capping adult returns at a level where juvenile populations would not be suppressed. Resume´ : Les gaspareaux (Alosa pseudoharengus) anadromes peuvent potentiellement modifier les bilans de nutriments des lacs cotiers pendant leurs migrations adultes vers les eaux douces et leurs migrations juveniles vers la mer. Les mon- taisons de gaspareaux sont generalement des sources de nutriments pour les lacs d'eau douce dans lesquels ils fraient, mais, dans les populations nouvellement retablies, les jeunes peuvent exporter plus de nutriments que les adultes n'en im- portent. Une montaison saine au Connecticut importe des quantites importantes de phosphore; la mortalitedes gaspareaux fournit 0,68 g Ppoisson -1 , alors que les poissons survivants apportent 0,18 g P, dont 67 % est de l'excretion. Actuellement, les gaspareaux fournissent 23 % de la charge annuelle de phosphore du lac Bride, mais cet apport etait beaucoup plus eleve ´ dans le passelorsque, durant les annees 1960, des montaisons plus importantes de poissons plus grands fournissaient 2,5 fois plus de phosphore. Une experience en mesocosme dans un lac adjacent montre que la croissance des gaspareaux est fortement relieeala densite ´, mais que la survie au debut du cycle est peut-etre trop faible pour que l'emigration des jeunes contrebalance les apports des adultes. Dans les systemes eutrophes dans lesquels les gestionnaires se preoccupent des nutri- ments, ceux-ci peuvent controler la charge de nutriments en limitant les retours d'adultes au niveau necessaire pour que les populations de jeunes ne soient pas reduites. (Traduit par la Redaction)
Isolation of lung tumor specific peptides from a random peptide library: Generation of diagnostic and cell-targeting reagents

Discovery of ligands specific to receptor(s) on a surface of a cancer cell could impact clinical issues including functional diagnosis and cell-specific drug delivery. Using a phage display approach, we have isolated 20-mer peptide ligands that bind to 3 different human lung tumor cell lines, NCI-H1299, NCI-H2009, and A549. The panning protocol is unbiased with no selection pressure towards binding a particular cellular receptor. The isolated phage bind to their target cells 24-300 times better than a control phage. Furthermore, the isolated peptides display remarkable cell-specificities and are able to discriminate between normal and cancerous cells as well as different lung tumor cells. The cell-specificities are not coincident with tumor classes indicating that the peptides are able to recognize cell-surface features that are not represented within the classification of tumor type. The isolated peptides are functional outside of the context of the phage and multimerization of the peptide increases its affinity for its given cell type, thus expanding their utility in clinical situations.
Participant satisfaction with a community-based medication synchronization program

Abstract Objective To assess participant satisfaction with a community pharmacy–based medication synchronization program. Setting A single location of a grocery store pharmacy chain in the Kansas City metropolitan area. Practice description A medication synchronization program, Time My Meds (TMM), was implemented in 1 of 20 community pharmacies within the grocery store chain. Practice innovation Current pharmacy patients taking three or more chronic medications were recruited to enroll in the medication synchronization program. After at least 3 months of enrollment in TMM, participants were invited to complete a paper survey to assess satisfaction with the program. Evaluation Data were collected on overall participant satisfaction with the TMM program. A 10-statement survey gathered demographic information and assessed participant satisfaction using a 5-point Likert scale (1, strongly disagree, to 5, strongly agree). Results Data collected from 48 surveys were analyzed. No statistical differences in participant satisfaction were found when considering age, education, income, number of medications at pick-up, or number of monthly trips to the pharmacy prior to program enrollment. Median scores for individual survey items were all 5 out of 5 (strongly agree) using a 5-point Likert scale. Conclusion Participants were highly satisfied with the medication synchronization program. These results, if expanded to a wider population, might provide valuable information for continued justification and implementation of this type of service in community pharmacies.
K-Ras and B-Raf oncogenes inhibit colon epithelial polarity establishment through up-regulation of c-myc.

KRAS, BRAF, and PI3KCA are the most frequently mutated oncogenes in human colon cancer. To explore their effects on morphogenesis, we used the colon cancer–derived cell line Caco-2. When seeded in extracellular matrix, individual cells proliferate and generate hollow, polarized cysts. The expression of oncogenic phosphatidylinositol 3-kinase (PI3KCA H1047R) in Caco-2 has no effect, but K-Ras V12 or B-Raf V600E disrupts polarity and tight junctions and promotes hyperproliferation, resulting in large, filled structures. Inhibition of mitogen-activated protein/extracellular signal–regulated kinase (ERK) kinase blocks the disruption of morphology, as well as the increased levels of c-myc protein induced by K-Ras V12 and B-Raf V600E. Apical polarity is already established after the first cell division (two-cell stage) in Caco-2 three-dimensional cultures. This is disrupted by expression of K-Ras V12 or B-Raf V600E but can be rescued by ribonucleic acid interference–mediated depletion of c-myc. We conclude that ERK-mediated up-regulation of c-myc by K-Ras or B-Raf oncogenes disrupts the establishment of apical/basolateral polarity in colon epithelial cells independently of its effect on proliferation.
EQUIVALENT INTRINSIC BLUR IN AMBLYOPIA

We used Gaussian blurred stimuli to explore the effect of blur on three tasks: (i) 2-line resolution; (ii) line detection; and (iii) spatial interval discrimination, in observers with amblyopia due to anisometropia, strabismus, or both. The results of our experiments can be summarized as follows. (i) 2-Line resolution: in normal foveal vision, thresholds for unblurred stimuli are approx. 0.5 min arc in the fovea. When the standard deviation (sigma) of the stimulus blur is less than 0.5 min, it has little effect upon 2-line resolution; however, thresholds are degraded when the stimulus blur, sigma, exceeds 0.5 min. We operationally define this transition point, as the equivalent intrinsic blur, or Bi. When the stimulus blur, sigma, is greater than Bi, then the resolution threshold is approximately equal to sigma. In all of the amblyopic eyes, 2-line resolution thresholds for unblurred stimuli were elevated, and the equivalent intrinsic blur was much larger. When the stimulus blur exceeds the equivalent intrinsic blur, resolution thresholds were similar in amblyopic and nonamblyopic eyes. (ii) Line detection: in both normal and amblyopic eyes, when the stimulus blur, sigma, is less than Bi, then the line detection threshold is approximately inversely proportional to sigma; i.e. (it obeys Ricco's law). When sigma is greater than Bi, the equivalent intrinsic blur, then the detection threshold is approximately a fixed contrast. All of the amblyopic eyes showed markedly elevated thresholds for detecting thin lines, but normal or near normal thresholds for detecting very blurred lines. Consequently, Ricco's diameter is larger in amblyopic than in normal eyes. (iii) Spatial interval discrimination: thresholds are proportional to the separation of the lines (i.e. Weber's law). At the optimal separation, spatial interval discrimination thresholds represent a "hyperacuity" (i.e. they are smaller than the resolution threshold). For unblurred lines, the optimal separation is approx. 2-3 times Bi. In the normal fovea, and in the amblyopic eyes of anisometropic amblyopes the optimal spatial interval discrimination threshold is about one-fifth of the resolution threshold (i.e. a hyperacuity); and over a wide range of separations, spatial interval discrimination thresholds begin to rise when the stimulus blur exceeds about one-third of the separation between the lines as long as the contrast is sufficiently high. In contrast, in strabismic amblyopes, like the normal periphery, the optimal spatial interval discrimination thresholds are worse (higher) than would be expected based upon the resolution limit of the strabismic amblyopic eye.(ABSTRACT TRUNCATED AT 400 WORDS)
Be aware of superbugs: Newspaper coverage of NDM-1 in India, UK, and the USA

ABSTRACTMarrying the psychometric paradigm with the community structure theory, this paper examines the coverage of a superbug (NDM-1) in newspapers in India, the UK, and the USA. It identifies several community structure characteristics: level of vested economic interest, level of health care available, and size of health care stakeholders as factors influencing how risks of NDM-1 are portrayed in terms of the level of dread, controllability, familiarity, and uncertainty. The finding provides baseline data for the scientific community and public health professionals in creating more effective messages to inform the public about the risks of superbugs.
Recurrence and Survival Outcomes after Percutaneous Thermal Ablation of Oligometastatic Melanoma

Abstract Objectives To evaluate focal treatment of melanoma metastases and to explore whether any potential extended survival benefit exists in a select patient population. Patients and Methods All patients who underwent image-guided local thermal ablation of metastatic melanoma over an 11-year period (January 1, 2002, to December 31, 2013) were retrospectively identified using an internally maintained clinical registry. Only patients with oligometastatic stage IV disease amenable to complete ablation of all clinical disease at the time of ablation were included in the analysis. Overall survival and median progression-free survival periods were calculated. Results Thirty-three patients with primary ocular or nonocular melanoma had 66 metastases treated in the lungs, liver, bones, or soft tissues. Eleven (33%) patients were on systemic medical therapy at the time of the procedure. The median survival time was 3.8 years (range, 0.5-10.5 years), with a 4-year estimated survival of 44.1% (95% CI, 28%-68%). Local recurrence at the ablation site developed in 15.1% (5 of 33) of the patients and 13.6% of the tumors (9 of 66). The median progression-free survival time was 4.4 months (95% CI, 1.4 months to 10.5 years), with an estimated 1-year progression-free survival of 30.3% (95% CI, 18%-51%). A subgroup analysis identified 11 patients with primary ocular melanoma and 22 with nonocular melanoma, with a median survival time of 3.9 years (range, 0.9-4.7 years) and 3.8 years (range, 0.5-10.5 years), respectively ( P =.58). There were no major complications and no deaths within 30 days of the procedure. Conclusion Selective use of image-guided thermal ablation of oligometastatic melanoma may provide results similar to surgical resection in terms of technical effectiveness and oncologic outcomes with minimal risk.
Permanent-Magnet Demagnetization Design and Validation

This paper investigates demagnetization characteristics of rare-earth permanent magnets (PMs) used in electric machines. A test fixture was designed and built to induce controllable local demagnetization in the magnet sample under test. A range of demagnetizing magnetomotive force (MMF) was applied to force the magnet samples to operate at various points along their B–H curves. The degree of demagnetization in the magnet samples was measured with a computer-controlled two-dimensional (2-D) flux mapping device. The measurements are compared with three-dimensional (3-D) finite-element analysis (FEA) simulations. This study results in greater insight into the capability of magnets to withstand various demagnetization forces and how spatially varying material properties affect this capability. The understanding gained from this study can be applied to the test and validation of the magnetic properties of the PMs used in the electric machines.
Measured Thomson Scattering from Diffuse Free Electrons in a Strong Laser Field

We report an absolute measurement of radiation emitted from free electrons emitted out the side of an intense laser focus. The measurement confirms the QED prediction that emitted radiation is independent of electron wave-packet size.
New Structures of Preceramic Polysilazanes Synthesized by Transition Metal Catalysis

Further capability of silazane dehydrocoupling polymerization catalyzed by ruthenium carbonyl (20–200 ppm) is demonstrated in a series of reactions. Ammonia and monomethylamine are used as reactants to bridge oligomers and polymers containing Si-H bonds to provide higher molecular weight polymers with higher latent reactivity and to increase the ceramic yields and the nitrogen-to-carbon ratio in the final ceramic compositions. New types of tractable polymers containing cyclomers having [MeSiHNH] units with molecular weights over 2000 d are formed. Various polymeric properties (e.g., viscosities, softening and melting points) and ceramic yields up to 80–85 wt% are obtained by controlling the catalytic reaction conditions.
Temporal Association Between Serum Gelsolin Levels and Clinical Events in a Patient with Severe Falciparum Malaria

Actin is present in high concentrations in most eukaryotic cells and can polymerize into filaments under physiological buffer conditions. As a result of tissue injury and cell lysis, large quantities of actin are released locally and may obstruct the downstream microvasculature, causing further damage to already injured organs. It has been postulated that this mechanism contributes to the development of the adult respiratory distress syndrome and to the diverse complications of falciparum malaria. Actin scavenging proteins--e.g., gelsolin--counteract the effects of extracellular actin, but the capacity of these plasma proteins can be overwhelmed by massive tissue injury. We examined the temporal relationship between serum levels of gelsolin (and tumor necrosis factor-alpha) and the clinical findings for a patient with severe falciparum malaria. The level of gelsolin decreased and then increased as the patient's status first worsened and then improved. We could not determine whether gelsolin served a biologically important function in this patient's recovery or was simply an epiphenomenon of disease activity. Gelsolin levels may be an early prognostic indicator in patients with a systemic inflammatory response syndrome. Moreover, the potential therapeutic role of recombinant human plasma gelsolin in patients with delayed organ dysfunction that commonly follows a self-limited initial insult merits investigation.
Chorioamnionitis and Early Brain Development

The association of chorioamnionitis and early postnatal risk factors for white matter injury (WMI) and its effect on early brain development were determined in a study at University of British Columbia, Vancouver, Canada.
The Source of Contamination of Heavy Metals in Dairy Products and Its Countermeasures

Contamination incidents of heavy metals in dairy products happened at home and abroad in recent years were reviewed.The source of contamination of heavy metals in dairy products was analyzed and its countermeasures of prevention and control were advised and prospected.
The determination of normal value and clinical significance for NSE in serum and CSF in children

Objective: To define the reference range for Neuron-specific enolase (NSE) in serum and cerebrospinal fluid (CSF) among different ages, and explore the relatoinship of NSE levels between in serum and in CSF among both healthy children and neonates with HIE, meanwhile, to discuss various kinds of factors having influence on the result of the test. Methods: The NSE levels in serum and CSF were measured by ELISA in healthy children and neonates with HIE. Results: The NSE levels in serum and CSF didn't correlated with sex and age in 66 healthy children. The specimen collection, preservation, dose of specimen and the process of operation were found as the factors influencing the test determination. The NSE levels in serum and CSF in neonates with HIE correlated greatedly with the severity of the patient's condition (t=2.95~6.38, P 0.01). The changes of NSE levels in serum of both heathy children and neonates with HIE were very correlated to those in CSF (r=83.5~87.3). Conclusion: Since the NSE levels in children's serum and CSF have no diffences in sex and age, only one normal value is needed for all children. The change of NSE level in serum can reflect the degree of neuron injury. The determination of NSE in serum and CSF can be used to estimate the severity of HIE in children, and to direct the treatment of these patients.
Protecting the private practice of medicine: direct primary care--Louisiana poised to lead.

As we discussed in our April editorial, “Direct Primary Care: Kicking Insurance Out of the Exam Room,” the new primary care practice model known as direct primary care (DPC) is posed to force an evolution of the healthcare system in Louisiana. DPC practices offer a membership-based approach to routine and preventive care, whereby patients pay a low monthly fee, typically $49 to $100, to their physician for all of their everyday health needs. DPC practices do not take insurance; therefore, there is no need for billing approval, deductibles, or co-payments. With lower overhead and dramatically less paperwork, providers have the time to deliver high-quality care instead of managing insurance claims. As of our April article, the Louisiana State Medical Society had introduced legislation, Senate Bill 516 authored by Senator Sherri Buffington and Representative Stuart Bishop, to make it possible to operate a direct primary care practice in Louisiana. Prior to this law being enacted on August 1, 2014, direct primary care practices would be subject to laws that regulate insurance companies because of their prepay model. After near unanimous support in both the house and senate, SB 516, now Act 867, cleared the regulatory path, allowing DPC practices to begin operating in Louisiana. In order to further educate our members about this important legislation, we have drafted a detailed summary of the legislation in hopes of expanding this practice model statewide.
Improved medication use in long-term care: building on the consultant pharmacist's drug regimen review.

Elderly and long-term care (LTC) patients often require complex medication regimens that increase their risk of adverse drug events or suboptimal pharmacotherapy. Currently, oversight of medication use in LTC facilities consists of a federally mandated monthly audit, the drug regimen review (DRR), performed by a consultant pharmacist, and yearly onsite government surveys. Although the DRR’s purpose is to improve drug use and to avoid adverse drug events, the Centers for Medicare and Medicaid Services’s (CMS) current DRR guidelines focus on a limited selection of medications and indications rather than on patient outcomes. An expanded model building on CMS’s survey guidelines and the American Society of Consultant Pharmacists’ Fleetwood Model is proposed to improve oversight of medication use. The proposed model includes using consultant pharmacists with demonstrated geriatric pharmacotherapy expertise, direct patient assessments by the pharmacist, increased interaction among healthcare professionals, evidence-based practices, and explicit patient outcome assessments. It is both feasible and timely: (1) the LTC prospective payment system aligns financial incentives between payers and providers; and (2) the Institute of Medicine has made quality improvement and error reduction a priority. (Am J Manag Care 2002;8:318-326)
Functional compartments of the yeast Golgi apparatus are defined by the sec7 mutation.

Abstract The role of the SEC7 gene product in yeast intercompartmental protein transport was examined. A spectrum of N-linked oligosaccharide structures, ranging from core to nearly complete outer chain carbohydrate, was observed on glycoproteins accumulated in secretion-defective sec7 mutant cells. Terminal alpha 1-3-linked outer chain mannose residues failed to be added to N-linked glycoproteins in sec7 cells at the restrictive temperature. These results suggest that outer chain glycosyl modifications do not occur within a single compartment. Additional evidence consistent with subdivision of the yeast Golgi apparatus came from a cell-free glycoprotein transport reaction in which wild-type membranes sustained outer chain carbohydrate growth up to, but not including, addition of alpha 1-3 mannose residues. Golgi apparatus compartments may specialize in addition of distinct outer chain determinants. The SEC7 gene product was suggested to regulate protein transport between and from functional compartments of the yeast Golgi apparatus.
Fever, abnormal white blood cell count, neutrophilia, and elevated serum C-reactive protein in adult hospitalized patients with bacteremia.

Objectives Relatively little is known about the prevalence of and factors associated with the absence of fever, normal white blood cell count (WBC), lack of neutrophilia, and the frequency of elevated serum C-reactive protein (CRP) in adult hospitalized patients with bacteremia. Methods Frequencies of fever (temperature ≥ 100°F), abnormal WBC count (≥ 10,000/μL or Results The frequencies of individual parameters were as follows: fever, 78.4% (95% confidence interval [CI] 74.9%-81.6%); abnormal WBC count, 65.2% (95% CI 61.3%-69.0%); neutrophilia, 67.5% (95% CI 63.7%-71.2%); and elevated CRP (>0.8 mg/dL), 98.4% (95% CI 97%-99.2%). Age 50 years and older, corticosteroid use, and isolation of either Staphylococcus sp not aureus or Enterococcus sp combined were independently associated with the absence of fever (P ≤ 0.01 for all). Isolation of Staphylococcus sp not aureus/Enterococcus and lack of corticosteroid use were independently associated with normal WBC (P Conclusions Absence of fever, normal WBC, and lack of neutrophilia are common in patients with bacteremia and may be confounded by a variety of factors; however, serum CRP remains elevated in the majority (>98%) of bacteremic episodes.
Imaging characteristics of cervical spine extra-arachnoid fluid collections managed conservatively

Determine the MRI characteristics of large post-traumatic cervical spine extra-arachnoid collections managed conservatively in clinically stable patients and whether evidence of clinical or imaging deterioration materialized. Following IRB approval, we conducted a retrospective search for all patients (>16 years old) over a 17-months period who had an extra-arachnoid fluid collection reported on a post-traumatic cervical spine MRI. Patients were excluded if they had surgery for an unstable fracture (n = 21), emergent decompression (n = 1) or lacked a follow-up MRI within 15 days (n = 1). Two MSK radiologists recorded the size, morphology and MRI signal characteristics of the collections. Eight patients (5 male, 3 female) met the inclusion criteria (mean age 40 years; range 19–78 years). Seven of the eight patients had fluid collections that demonstrated thin, tapered margins, extended >7 vertebral bodies and involved >180 degrees of the spinal canal. The signal characteristics of these collections varied: hyper-T1/iso-T2 (n = 1), iso-T1/T2 (n = 3), hyper-T1/hypo-T2 (n = 3) and mixed-T1/T2 (n = 1). Six of seven collections were ventral. Follow-up MRI demonstrated resolution/significant decrease in size (n = 4 between 1 and 12 days) or no change/slight decrease in size (n = 3; between 2 and 11 days). None of the seven fluid collections enlarged, no patient had abnormal cord signal, and no patient’s neurologic symptoms worsened. One of eight patients had a dorsal “mass-like” collection that was slightly smaller 9 days later. In stable patients with large, tapered post-traumatic cervical spine extra-arachnoid collections managed non-surgically, none developed (1) clinical worsening, (2) abnormal cord signal or (3) collection enlargement, regardless of the collection’s signal characteristics.
Editing Wyatt: The Letter and the Spirit

(1988). Editing Wyatt: The Letter and the Spirit. ANQ: A Quarterly Journal of Short Articles, Notes and Reviews: Vol. 1, No. 4, pp. 147-150.
Do oral contraceptives increase epileptic seizures

Introduction: Hormonal contraceptives are used by over 100 million people worldwide. Recently, there has been an emerging interest in studying the potential impact of oral contraceptives (OCs) on c...
Global warming projection in the 21st century based on an observational data-driven model

NSF [AGS-0944101]; NASA [NNX14AM02G]; Agnese Nelms Haury Program in Environment and Social Justice
A low-rank control variate for multilevel Monte Carlo simulation of high-dimensional uncertain systems

Abstract Multilevel Monte Carlo (MLMC) is a recently proposed variation of Monte Carlo (MC) simulation that achieves variance reduction by simulating the governing equations on a series of spatial (or temporal) grids with increasing resolution. Instead of directly employing the fine grid solutions, MLMC estimates the expectation of the quantity of interest from the coarsest grid solutions as well as differences between each two consecutive grid solutions. When the differences corresponding to finer grids become smaller, hence less variable, fewer MC realizations of finer grid solutions are needed to compute the difference expectations, thus leading to a reduction in the overall work. This paper presents an extension of MLMC, referred to as multilevel control variates (MLCV) , where a low-rank approximation to the solution on each grid, obtained primarily based on coarser grid solutions, is used as a control variate for estimating the expectations involved in MLMC. Cost estimates as well as numerical examples are presented to demonstrate the advantage of this new MLCV approach over the standard MLMC when the solution of interest admits a low-rank approximation and the cost of simulating finer grids grows fast.
Ethische Aspekte der refraktiven Chirurgie

Die refraktive Chirurgie ist aus zwei Grunden eine einzigartige Form von geplanter Operation: Es geht um einen so wichtigen und wertvollen Teil unseres Lebens: unser Augenlicht. Ein perfektes Ergebnis kann lebensverandernd sein, es kann dem Einzelnen die Moglichkeit geben, sich an neuen Aktivitaten zu beteiligen und die Welt auf eine andere Weise zu erleben. Umgekehrt kann ein schlechtes Operationsergebnis fur den Einzelnen verheerend sein, wegen der unnachgiebigen Auswirkungen auf das eigene Leben. Die refraktive Chirurgie verandert in den meisten Fallen die Funktion des Auges dauerhaft. Wichtig ist, dass einige Verfahren den Patienten von der Inanspruchnahme von zukunftigen Fortschritten in der Entwicklung der Technologien der Augenheilkunde ausschliesen. Das beste Beispiel hierfur ist der refraktive Linsenaustausch. Es ist sehr unwahrscheinlich, dass man zukunftig eine einmal implantierte Intraokularlinse durch eine voll funktionsfahige akkommodierende IOL wird ersetzen konnen.
Fünftes Kapitel. Topologie

Um die Mitte des 19. Jahrhunderts begann eine vollig neue Entwicklung in der Geometrie, die bald in der modemen Mathematik eine grose Rolle spielen sollte. Das neue Gebiet - Analysis Situs oder Topologie genannt - betrifft das Studium derjenigen Eigenschaften geometrischer Figuren, die selbst dann bestehen bleiben, wenn die Figuren so drastischen Deformationen unterworfen werden, das alle ihre metrischen und projektiven Eigenschaften verlorengehen.
Aging and Involution of the Immunological Apparatus

Thymic involution and involution of the thymus-dependent system of cells responsible for cell-mediated immunity (CMI) occur in man as they do in all animals that possess a thymus. Specific thymic alterations related to aging were described and extensively discussed by Hammar (1926) and have been reviewed by many others (Good and Gabrielson, 1964). It has been known for many years that beginning at the time of sexual maturation, an apparent programmed involution begins in the central lymphoid organs. This is succeeded by a period of gradual involution of the peripheral lymphoid apparatus and declining vigor of immunological functions (Walford, 1969; Roberts-Thomson et al., 1974; Yunis et al., 1968, 1971a,b; Stutman et al., 1968; Good and Yunis, 1974). In both man and mouse, the rate of immunological decline is highly variable. In aging research, fundamental questions to be answered focus on the determinants of variability in life span, i.e., longevity. The variability and thus the rate of immunological involution clearly implicate genetic determinants, as described later, but immunological involution, as with other aging processes, proceeds according to a schedule that fits a broad framework characteristic of the species.
Synthesis and evaluation of vitamin D3 analogues with C-11 modifications as inhibitors of Hedgehog signaling

Abstract Previous structure-activity relationship studies have provided potent and selective analogues of vitamin D3 as inhibitors of the Hedgehog (Hh) signaling pathway. These analogues contain both modified A- and seco -B ring motifs, and have been evaluated for anticancer therapeutic potential. To continue our studies on this scaffold, a new series of compounds were synthesized to explore additional interactions and spatial constraints. These compounds incorporate functional groups of varying size and hydrophobicity at the C-11 position. While large hydrophobic moieties ( 9c – e ) resulted in significant loss of Hh inhibition, smaller or more flexible moieties ( 9a , 11 ) maintain anti-Hh activity. These results call for additional and continued studies to identify the binding pocket to better understand these structure-activity relationships.
Origins of the Corporate Ideal in US Higher Education

The origins of the corporate university can be traced back to a corporate liberal political agenda first articulated during the American Progressive Era. The structure and processes of the corporate university were established from 1894–1928, and these institutional structures established the social form of the ideological state apparatus in the USA based on a concept of academic efficiency. A historical analysis argues that there have been three subsequent cycles of university corporatization from 1929–1952 and 1953–1989, and 1990 to the present. Each of these reform cycles in higher education has further advanced the corporate ideal at the expense of the academic ideal resulting in deeper penetration and stronger regulation of the university by corporate capital and the capitalist state.
Bacteriophage Distributions and Temporal Variability in the Ocean's Interior.

ABSTRACT Bacteriophages are numerically the most abundant DNA-containing entities in the oligotrophic ocean, yet how specific phage populations vary over time and space remains to be fully explored. Here, we conducted a metagenomic time-series survey of double-stranded DNA phages throughout the water column in the North Pacific Subtropical Gyre, encompassing 1.5 years from depths of 25 to 1,000 m. Viral gene sequences were identified in assembled metagenomic samples, yielding an estimated 172,385 different viral gene families. Viral marker gene distributions suggested that lysogeny was more prevalent at mesopelagic depths than in surface waters, consistent with prior prophage induction studies using mitomycin C. A total of 129 ALOHA viral genomes and genome fragments from 20 to 108 kbp were selected for further study, which represented the most abundant phages in the water column. Phage genotypes displayed discrete population structures. Most phages persisted throughout the time-series and displayed a strong depth structure that mirrored the stratified depth distributions of co-occurring bacterial taxa in the water column. Mesopelagic phages were distinct from surface water phages with respect to diversity, gene content, putative life histories, and temporal persistence, reflecting depth-dependent differences in host genomic architectures and phage reproductive strategies. The spatiotemporal distributions of the most abundant open-ocean bacteriophages that we report here provide new insight into viral temporal persistence, life history, and virus-host-environment interactions throughout the open-ocean water column. IMPORTANCE The North Pacific Subtropical Gyre represents one of the largest biomes on the planet, where microbial communities are central mediators of ecosystem dynamics and global biogeochemical cycles. Critical members of these communities are the viruses of marine bacteria, which can alter microbial metabolism and significantly influence their survival and productivity. To better understand these viral assemblages, we conducted genomic analyses of planktonic viruses over a seasonal cycle to ocean depths of 1,000 m. We identified 172,385 different viral gene families and 129 unique virus genotypes in this open-ocean setting. The spatiotemporal distributions of the most abundant open-ocean viruses that we report here provide new insights into viral temporal variability, life history, and virus-host-environment interactions throughout the water column.
Unique pulmonary immunotoxicological effects of urban PM are not recapitulated solely by carbon black, diesel exhaust or coal fly ash

Abstract Background Exposure to particulate matter (PM) is increasing worldwide as a result of increased human activity, the rapid industrialization of developing countries, and effects of climate change. Adverse effects of PM on human health are well documented, and because PM exposure occurs mostly through the airways, PM has especially deleterious impact on the lungs. Objective We investigated whether surrogate PM particles like carbon black (CB), diesel exhaust particle (DEP), coal fly ash (CFA) can recapitulate the allergic airway inflammatory response induced by urban particulate matter. Methods We compared the pro-inflammatory potential of urban PM collected from New York (NYC) and Baltimore (Balt) with CB, DEP and CFA surrogate PM particles. Eight to ten weeks old BALB/cJ mice were exposed through the airways to particulate material, and markers of airway inflammation were determined. Specifically, we assessed cellular influx, mucus production, lung function, cytokine levels as well as immune cell profiling of the lungs. Results Herein, we demonstrate that exposure to equivalent mass of stand-alone surrogate PM particles like CB, DEP and CFA, fails to induce significant airway inflammatory response seen after similar exposure to urban PMs. Specifically, we observe that PM collected from New York (NYC) and Baltimore city (Balt) triggers a mixed Th2/Th17 response accompanied by eosinophilic and neutrophilic influx, mucus production and airway hyperresponsiveness (AHR). Although the immune profile of NYC and Baltimore PMs are similar, they demonstrate considerable differences in their potency. Baltimore PM induced more robust airway inflammation, AHR, and Th2 cytokine production, possibly due to the greater metal content in Baltimore PM. Conclusions Urban particulate matter with its unique physiochemical properties and heterogeneous composition elicits a mixed Th2/Th17 allergic airway response that is not seen after similar exposures to surrogate PM particles.
Expectancy effects in the Autonomous Sensory Meridian Response.

The Autonomous Sensory Meridian Response (ASMR) is a tingling, almost euphoric, sensation often elicited following certain visual or auditory stimulations (Barratt & Davis, 2015). Despite considerable media attention, little empirical work has investigated the underlying mechanisms. In the present study, ASMR enthusiasts and naive observers listened to audio clips with and without ASMR-eliciting characteristics. We also manipulated participants' expectations of ASMR, providing a measure of "placebo effects." Although naive participants were susceptible to suggestive instructions, experienced users were not, suggesting that initial exposure to ASMR media may evoke somatosensory responses consistent with one's expectations. Implications for at-home stress management techniques are discussed.
Acinetobacter radioresistens infection with bacteremia and pneumonia

Acinetobacter species are non-fermentative Gram-negative coccobacilli that are ubiquitous in the environment. The archetype pathogen within the genus is Acinetobacter baumannii, however, other species have the potential to cause human infection, especially in the hospital setting. We describe a patient with infection due to Acinetobacter radioresistens, a rare agent of human disease, which is often misidentified using biochemical methods. Acinetobacter radioresistens is the source of the Class D OXA-23 carbapenemase that can confer carbapenem resistance in A. baumannii. Therefore, accurate identification of A. radioresistens is important for clinical management and to potentially prevent the spread of carbapenem resistance.
Cancer immunotherapy: Adoptive cell therapies, cytokine-related toxicities, and the kidneys:

Adoptive cell therapies represent a new frontier in the quest for potent, personalized therapies for malignant disease with fewer of the widespread adverse events associated with standard chemother...
Medications affecting the biochemical conversion to type 2 diabetes: A systematic review and meta-analysis.

Background The extent to which some pharmacological interventions reduce or increase the risk of biochemical conversion to T2DM in at-risk individuals is unclear. Methods We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and Scopus through August 24, 2017, for randomized controlled trials evaluating the effect of drugs suspected to modify the risk of biochemical conversion to T2DM. Results We included 43 trials with 192,156 subjects (mean age 60 years; 56% men; mean BMI 30.4 kg/m2). Alpha-glucosidase inhibitors, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, metformin, orlistat, phentermine-topiramate and pioglitazone significantly reduced the risk of biochemical conversion to T2DM, whereas statins and nateglinide increased the risk. There was insufficient direct evidence regarding the effects of sulfonylureas, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter-2 inhibitors. Most trials were brief and evaluated this outcome during treatment without a withdrawal or washout period. Conclusions Several drugs modify the risk of biochemical conversation to T2DM, although whether this effect is persistent and clinically relevant is unclear. Future studies need to focus on cardiovascular disease prevention, mortality and patient-important outcomes instead of biochemical conversion to T2DM.
Redundant Neurovascular Imaging: Who Is to Blame and What Is the Value?

BACKGROUND AND PURPOSE: Excessive use of neurovascular imaging studies such as Doppler ultrasound, CTA, MRA, and DSA adds cost to the evaluation of patients with new neurologic deficits. We sought to determine to what extent redundant neurovascular imaging is generated by radiologists’ recommendations and the agreement rates among modalities in this setting. MATERIALS AND METHODS: The radiology reports of 300 consecutive patients admitted for acute stroke to determine the frequency of the following: 1) >1 neurovascular study performed, 2) recommendation for another study, 3) recommendation made by the radiologist, and 4) agreement rates among these redundant neurovascular imaging studies. RESULTS: Among the 300 consecutive patients, 125 had redundant neurovascular imaging, accounting for 144 redundant studies. These included 75/125 redundant neurovascular imaging studies after MRA, 48/125 after CTA, and 2/125 after Doppler ultrasound. The radiologist recommended another vascular study in 22/125 (17.6%) patients; the rest of the recommendations were made by clinicians. The second study agreed with the first in 54.6% (12/22) of cases recommended by radiologists and 73.8% (76/103) recommended by clinicians (P value = .06). CTA agreed with MRA, carotid Doppler ultrasound, and DSA in 66.7%, 66.7%, and 55.6%, respectively. MRA agreed with Doppler ultrasound and DSA in 78.3% and 66.7%, respectively. CONCLUSIONS: Of cases with redundant neurovascular imaging, most were generated by clinicians, but radiologists recommended redundant neurovascular imaging in 17.6% of patients; 81.8% occurred following MRA. Overall, most secondary studies (68.8%) confirmed the findings of the first study. Such low-value, same-result redundant neurovascular imaging was more common when clinicians ordered the studies (73.8%) than when radiologists ordered them (54.6%).
Effect of 172-nm UV irradiation on polyimide and its application in surface modification by grafting:

Polyimides (PIs) have a wide range of industrial and scientific applications due to their excellent thermal and mechanical stability and chemical resistance. Their response to ultraviolet (UV) irra...
Theory of angle-resolved photoemission spectroscopy in graphene-based moiré superlattices

Graphene-based moir\'e superlattices are now established as an interesting platform for strongly correlated many-electron physics, and they have so far been characterized mainly by transport and scanning tunneling microscopy (STM) measurements. Motivated by recent experimental progress, we present a theoretical model study whose aim is to assess the potential of angle-resolved photoemission spectroscopy (ARPES) to resolve some of the many open issues in these systems. The theory is developed specifically for graphene on hexagonal boron nitride (G/hBN) and twisted bilayer graphene (TBG) moir\'e superlattices, but it is readily generalized to any system with active degrees of freedom in graphene sheets.
Patterns of National Institutes of Health Grant Funding to Surgical Research and Scholarly Productivity in the United States.

OBJECTIVE The aim of this study was to assess the contemporary trends in National Institutes of Health (NIH) grants awarded to surgical investigators, including potential disparities. BACKGROUND The NIH remains the primary public funding source for surgical research in the United States; however, the patterns for grants and grantees are poorly understood. METHODS NIH RePORTER was queried for new grants (R01, -03, -21) awarded to Departments of Surgery (DoS). Principal investigators' (PIs) data were extracted from publicly available information from their institutions' websites and/or professional social media accounts. RESULTS The NIH awarded 1101 new grants (total: $389,006,782; median: $313,030) between 2008 and 2018. Funding to DoS has doubled in the last 10 years ($22,983,500-2008 to $49,446,076-2018). Midwest/Southeast institutions and surgical oncologists accounted for majority of the grants (31.9% and 24.5%, respectively). Only 24.7% of the projects were led by female PIs, who were predominantly nonphysician PhD scientists (52% vs 37.7% PhD-only male PIs; P = 0.002). During this time, there was a significant increase from 12.4% to 31.7% in grants awarded to PIs with >15 years of experience. These grants were associated with 8215 publications; however, only 13.2% were published in high-impact journals (impact factor ≥10). 4.4% of the grants resulted in patents, and these were associated with higher award amounts ($345,801 vs $311,350; P = 0.030). On multivariate analysis, combined MD/PhD degree [odds ratio (OR) 5.98; 95% confidence interval (CI) 2.18-16.39; P < 0.001] was associated with improved odds of patent creation; conversely, practicing surgeon PIs affected patent creation negatively (OR 0.31; 95% CI 0.11-0.85; P = 0.024). CONCLUSION In the last decade, a greater proportion of NIH grants in DoS were awarded to more experienced investigators. Disparities exist among grantees, and female investigators are underrepresented, especially among practicing surgeons.