cssi/SciSciGPT-SciSciNet huggingface dataset:
Regulatory T Cells Control the Switch From in situ to Invasive Breast Cancer

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of breast cancer, and it only progresses to invasive breast cancer in around 40% of patients. While immune infiltrates have been observed in these early cancer lesions, their potential prognostic value is still unclear. Regulatory T (Treg) cells accumulate in advanced breast cancers, and predict poor outcome. We have shown before that ablation of Treg cells in established tumors leads to significant decrease in primary and metastatic tumor burden. In this work, we sought to investigate Treg cell function in the progression from non-invasive to invasive breast cancer lesions. To this end, we used the murine mammary tumor virus polyoma middle T (MMTV-PyMT) murine model of spontaneous, stage-wise breast carcinogenesis crossed to Foxp3 DTR knock in mice, allowing Treg cell ablation by administration of diphtheria toxin. Transient targeting of Treg cells at the in situ carcinoma stage resulted in a significant increase in the number of tumor-bearing mammary glands and size of growing tumors compared with control mice. Whole mammary gland mounts and histological examination confirmed larger emergent tumor area in Treg cell-ablated mice, and revealed that these tumors were characterized by a more advanced tumor staging, with presence of early invasion, increased desmoplasia and collagen deposition. Furthermore, Treg cell ablation increased the percentage of cancer stem/progenitor cells in the mammary compartment. Interestingly, Treg cell ablation resulted in increased inflammatory cytokines IL-4 and IL-5 with a concomitant reduction in classically activated tumor associated macrophages. This TH2-biased immune regulatory mammary inflammation was consistent with the enhancement in tumor promotion that we observed. Overall, our study demonstrates that Treg cells oppose breast cancer progression at early stages, raising a cautionary note regarding the consideration of immune intervention targeted at boosting immune responses for DCIS.
Morphology of Memory: Creating a web-based 3D interactive resource to teach the anatomy of the human hippocampus

The hippocampus is a critical region of the brain involved in memory and learning and is composed of layered, interconnected regions. Despite the importance of understanding normal hippocampal anatomy for studying its functions and disease processes that affect it, didactic educational visualizations are severely limited. To help graduate students and scientists better understand and visualize the human hippocampus, a web-based interactive resource was created that included a 3D animation and manipulatable 3D models of hippocampal regions. These resources allow users to expand their comprehension of this complex anatomy.
Smart City Ranking Reliability Analysis

Smart cities are the future of our life. More and smarter initiatives and projects have been proposed during the past decades. The smart city ranking results play an important role in the study of smart cities because the performance of smart cities is significant for political decision making, organizational strategy planning, human being career, and living choose. There are quite a few smart city ranking results available. Such kind of evaluation is important to the future development of smart cities. However, different rankings may not be consistent with each other, which necessities the need for evaluating the smart city rankings. In this paper, we apply reliability analysis to test the reliability of the current smart city ranking models. A chi-square test for homogeneity is adopted. Our finding shows that currently published ranking results are not reliable. We analyze the reasons for causing such a problem and call for a more systematic study on evaluation criteria of smart cities.
Functional mononuclear molybdenum enzymes: challenges and triumphs in molecular cloning, expression, and isolation

Mononuclear molybdenum enzymes catalyze a variety of reactions that are essential in the cycling of nitrogen, carbon, arsenic, and sulfur. For decades, the structure and function of these crucial enzymes have been investigated to develop a fundamental knowledge for this vast family of enzymes and the chemistries they carry out. Therefore, obtaining abundant quantities of active enzyme is necessary for exploring this family's biochemical capability. This mini-review summarizes the methods for overexpressing mononuclear molybdenum enzymes in the context of the challenges encountered in the process. Effective methods for molybdenum cofactor synthesis and incorporation, optimization of expression conditions, improving isolation of active vs. inactive enzyme, incorporation of additional prosthetic groups, and inclusion of redox enzyme maturation protein chaperones are discussed in relation to the current molybdenum enzyme literature. This article summarizes the heterologous and homologous expression studies providing underlying patterns and potential future directions.
Improving situational awareness with collective artificial intelligence over knowledge graphs

Situational awareness (SA) was defined as perception of environmental elements within the situation, comprehension, and projection of future status. Here the perception is the representation of sensory information that includes multi-typed interacting objects forming knowledge graphs." A typical problem in artificial intelligence (AI) research is to learn representations of objects that preserve structural information in knowledge graphs (KGs). Existing methods assume an AI agent has a complete knowledge graph, and any kind of prediction can be made accurately by a single AI. However, the real world needs multiple AI agents (e.g., warfighters, citizens) to collectively make a prediction. Each AI has a different, incomplete view of the knowledge graph with noise. In this work, I present a novel approach to improve representation learning and thus to improve SA with collective AI over KGs. I present the approach in four parts. First, I introduce knowledge graph and its nature of heterogeneity with multiple examples in the real world. Second, I discuss four ideas of making prediction with collective AI: prediction ensemble, data aggregation, representation aggregation, and joint representation learning. Third, I describe two state-of-the-art models to learn object representations from heterogeneous graphs: one is path- based embedding and the other is a graph neural network (GNN). Lastly, I present a new GNN framework that jointly learns object representations from multiple agents. Experimental results demonstrate that collective AI performs significantly better than individual AI. In future work, I discuss about federated learning that may improve security and privacy of the framework, which is quite necessary when any type of sharing (e.g., raw data, object representations, or learning process) is sensitive.
Assessment of the Radiology Support, Communication and Alignment Network to Reduce Medical Imaging Overutilization: A Multipractice Cohort Study.

Abstract Purpose The aim of this study was to determine whether participation in Radiology Support, Communication and Alignment Network (R-SCAN) results in a reduction of inappropriate imaging in a wide range of real-world clinical environments. Methods This quality improvement study used imaging data from 27 US academic and private practices that completed R-SCAN projects between January 25, 2015, and August 8, 2018. Each project consisted of baseline, educational (intervention), and posteducational phases. Baseline and posteducational imaging cases were rated as high, medium, or low value on the basis of validated ACR Appropriateness Criteria®. Four cohorts were generated: a comprehensive cohort that included all eligible practices and three topic-specific cohorts that included practices that completed projects of specific Choosing Wisely topics (pulmonary embolism, adnexal cyst, and low back pain). Changes in the proportion of high-value cases after R-SCAN intervention were assessed for each cohort using generalized estimating equation logistic regression, and changes in the number of low-value cases were analyzed using Poisson regression. Results Use of R-SCAN in the comprehensive cohort resulted in a greater proportion of high-value imaging cases (from 57% to 79%; odds ratio, 2.69; 95% confidence interval, 1.50-4.86; P = .001) and 345 fewer low-value cases after intervention (incidence rate ratio, 0.45; 95% confidence interval, 0.29-0.70; P Conclusions R-SCAN participation was associated with a reduced likelihood of inappropriate imaging and is thus a promising tool to enhance the quality of patient care and promote wise use of health care resources.
Hardware Implementation of Keyless Encryption Scheme for Internet of Things Based on Image of Memristors.

The Internet of Things (IoT) is rapidly increasing the number of connected devices. This causes new concerns towards solutions for authenticating numerous IoT devices. Most of these devices are resource-constrained. Therefore, the use of long-secret keys, in traditional cryptography schemes can be hard to implement. Also, the key generation, distribution, and storage are very complex. Moreover, the goal of many reported cyber-attacks is accessing the key. Therefore, researchers have shown an increased interest in designing keyless encryption schemes recently. In this report, we are going to explain the details of the implementation of the keyless protocol by taking advantage of known technology modules such as microcontrollers (MCU), and hash functions. Physical Unclonable Functions (PUFs) have been used in many cryptographic applications such as Password Management Systems, key exchange, Key Generation. In this report, we are going to explain the details of the hardware implementation of keyless encryption in the MCU. Different kinds of memristors have been used in the past. In this work, a look-up-table containing memristor cells value at the various current levels is used since the physical component is unavailable yet. The hardware that is used to implement the system is an evaluation-board of SAMV71 MCU, which is used to implement the control system and hardware hashing.
Autoimmune Hemolytic Anemia in Adolescent Females

Autoimmune hemolytic anemia (AIHA) is caused by antibody-mediated destruction of erythrocytes. AIHA may be primary or secondary to other underlying autoimmune conditions, immunodeficiencies, rheumatologic diseases, infections, or malignancies. The adolescent female is more likely to have secondary AIHA and may be more likely to have a chronic course. Treatment of AIHA in adolescent females necessitates careful consideration of side effects with particular attention to fertility issues and the possibility of pregnancy.
Slip delocalization and diffusion mediated carbide formation during fatigue of a nickel-base superalloy

Abstract Fatigue crack initiation at high temperatures occurs at microscopic fatigue shear bands that form near twin boundaries in polycrystalline nickel-base superalloys that contain minimal metallurgical defects. The associated dislocation sub-structure is complex and dependent on thermal and mechanical conditions. Here we show the formation of fine-scale carbide precipitates along these fatigue shear bands in a nickel-base superalloy during fatigue above 650 °C. The formation of carbide precipitates is studied using calculations of bulk and pipe diffusion. The contribution of pipe diffusion is observed to be critical in the formation of fine-scale carbides and occurs coincident with the delocalization of slip during fatigue.
Independence versus abandonment among people with visual impairments in puerto rico throughout the 2017 hurricane season

Two major themes emerged from a qualitative case study on the 2017 hurricane season in Puerto Rico and its impact on people with visual impairments. The first theme was independence as it related t...
Age and insulin-like growth factor-1 impact PCNA monoubiquitination in UVB-irradiated human skin.

Nonmelanoma skin cancers occur primarily in individuals over the age of 60 and are characterized by an abundance of ultraviolet (UV) signature mutations in keratinocyte DNA. Though geriatric skin removes UV photoproducts from DNA less efficiently than young adult skin, it is not known whether the utilization of other prosurvival but potentially mutagenic DNA damage tolerance systems such as translesion synthesis (TLS) is altered in older individuals. Using monoubiquitination of the replicative DNA polymerase clamp protein PCNA (proliferating cell nuclear antigen) as a biochemical marker of TLS pathway activation, we find that UVB exposure of the skin of individuals over the age of 65 results in a higher level of PCNA monoubiquitination than in the skin of young adults. Furthermore, based on previous reports showing a role for deficient insulin-like growth factor-1 (IGF-1) signaling in altered UVB DNA damage responses in geriatric human skin, we find that both pharmacological inhibition of the IGF-1 receptor (IGF-1R) and deprivation of IGF-1 potentiate UVB-induced PCNA monoubiquitination in both human skin ex vivo and keratinocytes in vitro. Interestingly, though the TLS DNA polymerase Pol eta can accurately replicate the major photoproducts induced in DNA by UV radiation, we find that it fails to accumulate on chromatin in the absence of IGF-1R signaling and that this phenotype is correlated with increased mutagenesis in keratinocytes in vitro. Thus, altered IGF-1/IGF-1R signaling in geriatric skin may predispose epidermal keratinocytes to carry out a more mutagenic form of DNA synthesis following UVB exposure.
Preventing adolescent risky sexual behavior: parents matter!

Family-Centered Care provides a forum for sharing information about basic components of caring for children and families, including respect, information sharing, collaboration, family-to-family support, and confidence building.
Chiral matter multiplicities and resolution-independent structure in 4D F-theory models

Motivated by questions related to the landscape of flux compactifications, we combine new and existing techniques into a systematic, streamlined approach for computing vertical fluxes and chiral matter multiplicities in 4D F-theory models. A central feature of our approach is the conjecturally resolution-independent intersection pairing of the vertical part of the integer middle cohomology of smooth elliptic CY fourfolds, relevant for computing chiral indices and related aspects of 4D F-theory flux vacua. We illustrate our approach by analyzing vertical flux backgrounds for F-theory models with simple, simply-laced gauge groups and generic matter content, as well as models with U(1) gauge factors. We explicitly analyze resolutions of these F-theory models in which the elliptic fiber is realized as a cubic in $\mathbb P^2$ over an arbitrary (e.g., not necessarily toric) smooth base, and confirm the resolution-independence of the intersection pairing of the vertical part of the middle cohomology. In each model we study, we find that vertical flux backgrounds can produce nonzero multiplicities for all anomaly-free chiral matter field combinations, suggesting that F-theory geometry imposes no additional linear constraints beyond those implied by anomaly cancellation.
Aerodynamic Shape Optimization Methods

Although fast and accurate in creating aerodynamic shapes compatible with the specified surface pressure distribution, the inverse shape design methods create configurations that are not optimal even at the design operating conditions [163], [164]. At off design conditions, these configurations often perform quite poorly except when the specified surface pressure distribution, if available at all, would be provided by an extremely accomplished aerodynamicist. When using inverse shape design methods, it is physically unrealistic to generate a 3-D aerodynamic configuration that simultaneously satisfies the specified surface distribution of flow variables, manufacturing constraints (smooth variation of a lifting surface sweep and twist angles, smooth variation of its taper, etc.) and achieves the best global aerodynamic performance (overall total pressure loss minimized, lift/drag maximized, etc.). The designer should use an adequate global optimization algorithm that can utilize any available flow-field analysis code without changes and efficiently optimize the overall aerodynamic characteristics of the 3-D flight vehicle subject to the finite set of desired constraints. The constraints could be purely geometrical or they can be of the overall aerodynamic nature (minimize overall drag for the given values of flight speed, angle of attack and overall lift force, etc.). These objectives can only be met by performing an aerodynamic shape constrained optimization instead of an inverse shape design.
WE-D-BRB-00: Modeling Cancer Complexity

Discoveries in cancer research are impacting patients through development of new therapeutics and better diagnostic tools. However, there is still a lack of understanding about heterogeneity in patient response to these therapeutics, optimizing therapeutic dosing schedules, or predicting complex metastatic patterns due to the complexity of the disease. Heterogeneity of patient response to treatment stems from the intricate interactions with the microenvironment, and distant organs and other environmental pressures including low oxygen, high acidity, and toxic drugs. To deconvolute some of this complexity physical scientists are using intricate tools to improve cancer diagnosis and predict drug resistance. Also to predict tumor growth and response to therapeutics, computational scientists are developing mathematical tools that link physical sciences or evolutionary sciences approaches with experimental and clinical data. These models yield predictions based on initial parameters obtained from patient clinical data, such as noninvasive imaging. This session will highlight the utilization of these mathematical and physical tools to predict patient response to treatment options, predict the optimal drug dosing schedule, and improve cancer diagnosis. This approach could be further enhanced by developing tools and models to chart the progress of stressed, aging tissue towards the progression to uncontrolled cell growth and mutational meltdown even before the diagnosis. Learning Objectives: 1. To learn about treatment response heterogeneity 2. To learn about tumor evolutionary capabilities 3. To learn about mathematical tools that link physical sciences with experimental and clinical data
Order statistics-based unbiased homomorphic system to reduce multiplicative noise

In this paper, we propose an order statistics-based unbiased homomorphic system to reduce multiplicative noise. The design of such a system is based on the probability density function (PDF) of the noise. First, we generalize the order statistics-based nonlinear filter called the sampled function weighted order (SFWO) filter proposed in [1] to reduce additive noise, to the case when the additive noise is not symmetric. This generalized SFWO (GSFWO) filter is then used in a homomorphic system to reduce multiplicative noise corrupting a signal. It is shown that the output from this GSFWO filter-based homomorphic system will be biased and hence, a bias compensation technique is applied to the output to get the unbiased estimate. A study of the qualitative and quantitative performance of the proposed GSFWO filter-based unbiased homomorphic system in reducing multiplicative noise is carried out and compared to that of some of the existing ones. It is found that the proposed GSFWO filter-based system consistently outperforms the others irrespective of the type of the PDF of the multiplicative noise.
Heinz von Foerster's heuristics course: A factor in the development of second‐order cybernetics in the United States

Purpose – The purpose of this paper is to investigate how the heuristics course co‐taught by Heinz von Foerster, Herbert Brun, and Humberto Maturana (1968‐1969) influenced cybernetic research in the USA.Design/methodology/approach – The author accessed the archived material from three sources: the Herbert Brun Library, the University of Illinois Library, and the Biological Computer Laboratory (BCL) and interpreted these materials in light of the cybernetics literature, and the publications of the American Society for Cybernetics (ASC).Findings – The heuristics course had major consequences in von Foerster's evolving critique of education, and in Brun's work towards founding a School for Designing a Society. von Foerster radically reoriented the BCL toward unconventional course proposals. He also began to critique objectivity and positivism, shifting the foundations of cybernetics and proposing a meta‐cybernetics. The year that von Foerster retired, the BCL and the ASC ceased to function. When the ASC retu...
Is S Phase Important for Transcriptional Silencing

Because the silencing of chromatin is dependent on passage of cells through S phase, it has always been assumed that DNA replication is a prerequisite for transcriptional silencing. Now, as [Smith and Boeke][1] explain in their Perspective, new work in yeast ([ Li et al. ][2], [Kirchmaier and Rine][3]) demonstrates that DNA replication is not required for establishing silencing of chromatin in yeast, although it may be crucial for maintenance or heritability of the silent state. [1]: http://www.sciencemag.org/cgi/content/full/291/5504/608 [2]: http://www.sciencemag.org/cgi/content/short/291/5504/650 [3]: http://www.sciencemag.org/cgi/content/short/291/5504/646
FLASCHE – a mechanism providing anonymity for mobile users

The protection goal anonymity helps to preserve the privacy of us ers by ensuring that their identity remains unknown. Many mechanisms ena bling anonymity exist. However, these mechanisms work inefficiently when used in mobile wireless networks. This contribution shows how anonymity can be provided efficiently for mobile users by exploiting the fact that they are mobile. A possible realization, called FLASCHE, is described.
Implementation of outcomes assessment in a large engineering program

Georgia Institute of Technology is one of five institutions that participated in pilot evaluations under ABET Engineering Criteria 2000. This paper describes the assessment process used by the School of Electrical and Computer Engineering, including the definition of objectives and outcomes, implementation of assessment measures, and efforts to use the assessment results for continuous improvement. Preparations for the pilot visit and "lessons learned" also are described.
A layered approach to complex negotiations

In this paper, we present a layered agent framework in which the negotiation process is performed at different levels of abstractions. In a real time, multiple-tasking, resource-bounded environment, negotiation is not an isolated process but one that interleaved with agent's many other activities, such as scheduling, execution, and other negotiations. To make the complexities of negotiation more tractable, the negotiation process is performed at two abstraction levels to reduce the complexity of the search. The upper level deals with the formation of high-level goals and objectives for the agent, and the decision about whether or not to negotiate with other agents to achieve particular goals, in what order the multiple related negotiations should be performed, and what negotiation attitude should be used for each negotiation. Negotiation at this upper level determines the rough scope of the commitment (i.e. the time and the quality characteristics) and the cost of the commitment. The lower level deals with feasibility and implementation operations, such as the detailed analysis of candidate tasks and actions and the formation of the detailed temporal/resource-specific commitments among agents; negotiation at this level involves refinement of the rough commitments proposed at the upper level. The experimental work shows this two-level negotiation framework enables the agent to handle complicated negotiation issues and uncertainties in a more efficient way.
Multipolar representation of protein structure

That the structure determines the function of proteins is a central paradigm in biology. However, protein functions are more directly related to cooperative effects at the residue and multi-residue scales. As such, current representations based on atomic coordinates can be considered inadequate. Bridging the gap between atomic-level structure and overall protein-level functionality requires parameterizations of the protein structure (and other physicochemical properties) in a quasi-continuous range, from a simple collection of unrelated amino acids coordinates to the highly synergistic organization of the whole protein entity, from a microscopic view in which each atom is completely resolved to a "macroscopic" description such as the one encoded in the three-dimensional protein shape. Here we propose such a parameterization and study its relationship to the standard Euclidian description based on amino acid representative coordinates. The representation uses multipoles associated with residue Cα coordinates as shape descriptors. We demonstrate that the multipoles can be used for the quantitative description of the protein shape and for the comparison of protein structures at various levels of detail. Specifically, we construct a (dis)similarity measure in multipolar configuration space, and show how such a function can be used for the comparison of a pair of proteins. We then test the parameterization on a benchmark set of the protein kinase-like superfamily. We prove that, when the biologically relevant portions of the proteins are retained, it can robustly discriminate between the various families in the set in a way not possible through sequence or conventional structural representations alone. We then compare our representation with the Cartesian coordinate description and show that, as expected, the correlation with that representation increases as the level of detail, measured by the highest rank of multipoles used in the representation, approaches the dimensionality of the fold space. The results described here demonstrate how a granular description of the protein structure can be achieved using multipolar coefficients. The description has the additional advantage of being immediately generalizable for any residue-specific property therefore providing a unitary framework for the study and comparison of the spatial profile of various protein properties.
A neutron diffraction study of Cp2Ti{(μ-H)2BC8H14}

Abstract The structure of Cp2Ti{(μ-H)2BC8H14} has been determined by single-crystal neutron diffraction methods. The geometrical parameters of the central four-atom core, Ti(μ-H)2B, are: TiH=1.904(15), 1.933(17) A; BH=1.298(15), 1.333(13) A; TiHB=94.1(8)°, 96.7(9)°; HTiH=65.3(6)°, HBH=103.8(9)°; Ti⋯B=2.426(12) A; H⋯H=2.071(19) A. The final weighted agreement factor is Rw=8.7% for 2635 unique reflections collected at 20 K from a crystal of volume 0.8 mm3 at the Argonne Intense Pulsed Neutron Source (IPNS). This structure determination represents the first neutron diffraction analysis of a TiH bonding distance in a molecule, as well as the first neutron analysis of a TiHB bridge bond.
Perforation of a nasoseptal flap does not increase the rate of postoperative cerebrospinal fluid leak.

Background The nasoseptal flap (NSF) has been shown to be a valuable addition to the reconstructive armamentarium of the endoscopic skull-base surgeon. We aimed to evaluate the rate of postoperative cerebrospinal fluid (CSF) leak after use of a NSF that had a small tear during harvest. Methods After Institutional Review Board (IRB) approval, we analyzed our database of patients undergoing skull-base resection. We included all patients who had a NSF reconstruction, septoplasty, and/or spur on preoperative computed tomography (CT) imaging. We then evaluated video of each procedure to determine if a tear occurred in the NSF during harvest. Patient records were reviewed to determine if a postoperative CSF leak occurred. Results We evaluated video of 21 patients who underwent a skull-base resection, were reconstructed with a NSF, and had either a septoplasty or evidence of a septal spur on CT imaging. Of these 21 cases, 11 small tears occurred during harvest of the NSF flap and none of the patients with a torn NSF had a postoperative CSF leak. Conclusion Our series shows a 0% postoperative CSF leak rate in patients undergoing skull-base reconstruction with a NSF that was torn during harvest. Small tears in the NSF do not seem to affect postoperative CSF leak rates.
Pharmacologic Actions of the Second-Generation Leukotriene B4 Receptor Antagonist LY293111: In Vitro Studies

We examined the in vivo actions of LY293111 sodium (2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]pro poxy]phenoxy] benzoic acid sodium salt). Guinea pigs were used to evaluate the effect of this agent on (1) acute airway obstruction produced by intravenous leukotriene B4, (2) pulmonary granulocyte infiltration and delayed onset airway obstruction resulting from a 4-h leukotriene B4 inhalation and (3) lung inflammation after aerosol challenge with the divalent cationic ionophore A23187 (6S-[6alpha(2S*,3S*),8beta(R*),9beta,11alpha]-5- (methylamino)-2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1H-pyrrol-2-yl)e thyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazole carboxylic acid). Airway obstruction was quantitated using pulmonary gas trapping measurements and lung inflammation was evaluated by bronchoalveolar lavage (BAL) and histology. LY293111 sodium produced a dose-related inhibition of acute leukotriene B4-induced airway obstruction when administered i.v. (ED50=14 microg/kg) or p.o. (ED50=0.4 mg/kg). In contrast, LY293111 sodium did not inhibit the pulmonary gas trapping caused by aerosols of histamine, leukotriene D4, or the thromboxane mimetic U46619 (15 [(S)-hydroxy11a,9a-(epoxymethano)prosta-5Z,13E-dienoic acid]). Oral LY293111 sodium inhibited leukotriene B4-induced bronchoalveolar lavage granulocyte infiltration and delayed onset airway obstruction at doses as low as 0.3 mg/kg. In A23187-challenged animals, pulmonary inflammation was markedly inhibited at 1 h, but not 2 h and 4 h post-exposure. We conclude that LY293 11 sodium is a selective leukotriene B4 receptor antagonist with potent pulmonary anti-inflammatory activity.
Pharmacological Modulation of Photoreceptor Outer Segment Degradation in a Human iPS Cell Model of Inherited Macular Degeneration

Degradation of photoreceptor outer segments (POS) by retinal pigment epithelium (RPE) is essential for vision, and studies have implicated altered POS processing in the pathogenesis of some retinal degenerative diseases. Consistent with this concept, a recently established hiPSC-RPE model of inherited macular degeneration, Best disease (BD), displayed reduced rates of POS breakdown. Herein we utilized this model to determine (i) if disturbances in protein degradation pathways are associated with delayed POS digestion and (ii) whether such defect(s) can be pharmacologically targeted. We found that BD hiPSC-RPE cultures possessed increased protein oxidation, decreased free-ubiquitin levels, and altered rates of exosome secretion, consistent with altered POS processing. Application of valproic acid (VPA) with or without rapamycin increased rates of POS degradation in our model, whereas application of bafilomycin-A1 decreased such rates. Importantly, the negative effect of bafilomycin-A1 could be fully reversed by VPA. The utility of hiPSC-RPE for VPA testing was further evident following examination of its efficacy and metabolism in a complementary canine disease model. Our findings suggest that disturbances in protein degradation pathways contribute to the POS processing defect observed in BD hiPSC-RPE, which can be manipulated pharmacologically. These results have therapeutic implications for BD and perhaps other maculopathies.
Frailty and the aging male.

Frailty occurs in aging males for a variety of reasons. It is less common in males than females. Diseases which are particularly associated with frailty are diabetes mellitus, atherosclerosis, anemia and chronic obstructive pulmonary disease. Insulin resistance syndrome plays a pathogenetic role in the “fat-frail” syndrome. Sarcopenia occurs predominantly because of hormone deficiency and cytokine excess. Pain and anorexia are also associated with frailty. Stem cell research represents a potential promise for the treatment of frailty.
Evidence for a thyroid peroxidase associated “active iodine” species

Abstract The role of thyroid peroxidase (donor:hydrogen-peroxide oxidoreductase, EC 1.11.1.7) in tyrosyl iodination has been investigated using a tripeptide substrate, α- l -glutamyl- l -tyrosyl- l -glutamic acid (Glu-Tyr-Glu). Competition experiments performed with thyroid peroxidase and several iodide acceptors indicate that there is a site for these substrates on the enzyme. The rates of three reactions, peroxidase catalyzed iodination of Glu-Tyr-Glu, chemical iodination of the same tripeptide and peroxidase catalyzed production of iodine were measured as a function of pH, and were found to be different from one another, indicating that the enzymic iodinating species is not free iodine. An iodinating species was demonstrated to be peroxidase-associated: This species was generated by incubation of the enzyme with iodide-125 and hydrogen peroxide. The labeled intermediate was separated from low molecular weight reaction components by gel filtration and was shown capable of iodinating Glu-Tyr-Glu in the absence of added iodide or peroxide. The iodinated product, Glu-Tyr(I)-Glu was identified by thin layer chromatography and radio-autography. These results support the idea that thyroid peroxidase plays a direct catalytic role in iodination. Iodination does not occur by way of free iodine generated by the enzyme and released into the medium, but rather via an iodinating species associated with the enzyme.
Dynamic template-matching-based processing for handheld landmine detector

This paper investigates the use of landmine templates in the GPR data to improve the detection accuracy for a hand-held mine detection unit. The proposed algorithm applies to the discrimination operating mode after the initial detection from the search mode. The proposed template matching-based algorithm extracts the mine templates from the data acquired during the first few sweeps, and correlates the templates from the data at subsequent sweeps to enhance the detection of landmine. The proposed technique does not have a time lag in producing detection values and a detection value is generated at each sample location. Experimental results show that the proposed template matching-based detector is able to increase the detection especially for low-metal anti-personnel mines. Based on the experiment performed over the data set collected at a test site, at 95% Pd, the proposed algorithm reduces the probability of false alarms by 66% for the low-metal anti-personnel mines and 30% for the low-metal anti-tank mines.
Polycyclic aromatic hydrocarbon exposures of children in low-income families.

Children in low-income families may have high exposures to polycyclic aromatic hydrocarbons (PAH). Such exposures could result from household proximity to heavy traffic or industrial sources, environmental tobacco smoke, contaminated house dust or soil, among others. The objectives of this study were: to establish methods for measuring total PAH exposure of children in low-income families, to estimate the PAH exposures of these children, and to estimate the relative importance of the environmental pathways for PAH exposure. Analytical methods to determine PAH in air, dust, soil, and food and to determine hydroxy-PAH in urine samples were evaluated and validated. A two-home pilot study was conducted in downtown Durham, North Carolina (NC) during February 1994. One smoker's and one nonsmoker's household, which had preschool children and income at or below the official U.S. poverty level, participated. A nine-home winter and a nine-home summer study were conducted in Durham and the NC Piedmont area during February 1995 and August 1995, respectively. A summer study in four smokers' homes was also conducted. In each of these studies, multimedia samples were collected and analyzed for PAH or hydroxy-PAH. Summary statistics, Pearson correlations, and analysis of variance were performed on the combined data from these four field studies. An effective screening method was established for recruiting low-income families. The field protocol involved measurements of three homes in 2-day periods. This protocol should be suitable for large-scale studies. The results showed that indoor PAH levels were generally higher than outdoor PAH levels. Higher indoor PAH levels were observed in the smokers' homes compared to nonsmokers' homes. Higher outdoor PAH levels were found in inner city as opposed to rural areas. The relative concentration trend for PAH in dust and soil was: house dust > entryway dust > pathway soil. The PAH concentrations in adults' food samples were generally higher than those in children's food samples. Children's potential daily doses of PAH were higher than those of adults in the same household, when intakes were normalized to body weights. Inhalation is an important pathway for children's exposure to total PAH because of the high levels of naphthalene present in both indoor and outdoor air. Dietary ingestion and nondietary ingestion pathways became more important for children's exposure to the B2 PAH (ranked as probable human carcinogens, B2 by the U.S. EPA's Integrated Risk System), most of which are of low volatility. The analysis of variance results showed that inner city participants had higher total exposure to B2 PAH than did rural participants.
Linkage Diplomacy: Economic and Security Bargaining in the Anglo-Japanese Alliance, 1902–23

How do states use economic-security linkages in international bargaining? Governments can provide economic benefits as a side payment to reinforce security cooperation and use close security ties a...
A Schur complement inequality for certain P-matrices

Abstract Suppose A and B are n × n matrices over the complex field. An inequality is derived that relates the Schur complement of the Hadamard product of A and B and the Hadamard product of Schur complements of A and B for positive definite matrices. Then an analog is given for the class of tridiagonal totally nonnegative matrices. A similar result is given for classes of Z -matrices where the Hadamard product is replaced by the Fan product.
DiRTlib: A Library to Add an Overset Capability to Your Flow Solver

The modifications to a flow solver to add an overset capability can be an impediment to developers wishing such a capability. The Donor interpolation Receptor Transaction library (DiRTlib) is a solver neutral library that simplifies the addition of an overset capability to a flow solver by encapsulating the required operations. This paper discusses the design issues of such a general capability and details the use of DiRTlib in a solver.
Neuronal Death and Perinatal Lethality in Voltage-Gated Sodium Channel αII-Deficient Mice

Neural activity is crucial for cell survival and fine patterning of neuronal connectivity during neurodevelopment. To investigate the role in vivo of sodium channels (NaCh) in these processes, we generated knockout mice deficient in brain NaChalpha(II). NaChalpha(II)(-/-) mice were morphologically and organogenically indistinguishable from their NaChalpha(+/-) littermates. Notwithstanding, NaChalpha(II)(-/-) mice died perinatally with severe hypoxia and massive neuronal apoptosis, notably in the brainstem. Sodium channel currents recorded from cultured neurons of NaChalpha(II)(-/-) mice were sharply attenuated. Death appears to arise from severe hypoxia consequent to the brainstem deficiency of NaChalpha(II). NaChalpha(II) expression is, therefore, redundant for embryonic development but essential for postnatal survival.
Structural changes in the skin of hairless mice following exposure to sulfur mustard correlate with inflammation and DNA damage

Sulfur mustard (SM, bis(2-chloroethyl)sulfide) is a bifunctional alkylating agent that causes dermal inflammation, edema and blistering. To investigate the pathogenesis of SM-induced injury, we used a vapor cup model which provides an occlusive environment in which SM is in constant contact with the skin. The dorsal skin of SKH-1 hairless mice was exposed to saturated SM vapor or air control. Histopathological changes, inflammatory markers and DNA damage were analyzed 1–14 days later. After 1 day, SM caused epidermal thinning, stratum corneum shedding, basal cell karyolysis, hemorrhage and macrophage and neutrophil accumulation in the dermis. Cleaved caspase-3 and phosphorylated histone 2A.X (phospho-H2A.X), markers of apoptosis and DNA damage, respectively, were increased whereas proliferating cell nuclear antigen (PCNA) was down-regulated after SM exposure. By 3 days, epithelial cell hypertrophy, edema, parakeratosis and loss of epidermal structures were noted. Enzymes generating pro-inflammatory mediators including myeloperoxidase and cyclooxygenase-2 were upregulated. After 7 days, keratin-10, a differentiation marker, was evident in the stratum corneum. This was associated with an underlying eschar, as neoepidermis began to migrate at the wound edges. Trichrome staining revealed increased collagen deposition in the dermis. PCNA expression in the epidermis was correlated with hyperplasia, hyperkeratosis, and parakeratosis. By 14 days, there was epidermal regeneration with extensive hyperplasia, and reduced expression of cleaved caspase-3, cyclooxygenase-2 and phospho-H2A.X. These findings are consistent with the pathophysiology of SM-induced skin injury in humans suggesting that the hairless mouse can be used to investigate the dermatoxicity of vesicants and the potential efficacy of countermeasures.
Inferring relative popularity of internet applications by actively querying DNS caches

In this work, we propose a novel methodology that can be used to assess the relative popularity for any Internet application based on the data servers it uses. The basic idea is to infer popularity of data servers by periodically "poking" at local Domain Name servers (LDNSs) that service Domain Name System requests from a set of users running Internet applications and determining if LDNSs have cached resource records for the data servers. This approach allows us to measure the relative percentage of pokes that result in a cache hit as a coarse measure of the relative popularity of a particular data server among the users of a given LDNS. In addition, the time-to-live (TTL) of cached DNS resource records can be used to measure the gaps in time when a resource record for a data server is not cached. The cache gaps can be used to infer request interarrivals for more popular data servers.The methodology can be applied to any Internet application that uses distinguished server names and performs DNS lookups on these names as part of application use. The methodology can be used to collect usage information from any LDNS that accepts DNS queries. As example applications of the methodology, we evaluate the relative popularity of selected Web sites and the relative popularity of different Web servers serving content at a given Web site. We also apply the methodology to servers providing multimedia content, data servers for grid computing, and network game servers. We use data gathered from LDNSs of commercial and educational sites as well as Internet Service Providers serving both commercial and home customers.
Synthesis of the C21–C34 fragment of antascomicin B

The C21–C34 fragment of the potent FKBP12-binding macrolide antascomicin B was prepared using Ireland-Claisen and allylic diazene rearrangements to establish the C26/C27 and the C23 stereocenters, respectively. Directed hydrogenation installed the C29 β-configuration. The fragment possesses 7 of the 11 fixed stereocenters contained in the natural product.
Identification of the α and β subunits of the chloroplast coupling factor one in Chlamydomonas reinhardi

The α and β subunits of the Chlamydomonas reinhardi coupling factor one have been identified by an immunochemical method and by the reaction of dicyclohexylcarbodiimide with the β subunit. Antibodies raised against the C. reinhardi subunit with the highest apparent molecular weight react with the α subunit of spinach coupling factor one and antibodies raised against the β subunit of the spinach chloroplast enzyme cross-react with the C. reinhardi subunit of lower apparent molecular weight. Dicyclohexylcarbodiimide also reacts with this subunit. We conclude therefore that the two subunits of highest apparent molecular weight can be named α and β in order of decreasing apparent molecular weight, in contrast to the nomenclature suggested by Piccioni, R. G., Bennoun, P. and Chua, N.-H. [(1981) Eur. J. Biochem. 117, 93–102].
English-medium degree programs in Japanese universities: learning from the European experience

Purpose – The purpose of this paper is to examine the challenges facing Japanese institutions of higher education wishing to implement degree programs taught through the medium of English. Design/methodology/approach – The paper takes a comparative perspective in examining the rationales and policies for, and the challenges and successes associated with, the adoption of English-medium instruction (EMI) in Japan and in Europe, where EMI has a longer history. It uses government policy declarations and reports and synthesizes the research literature and information published by universities. Next, it investigates the practices that apply to the Japanese context and provides recommendations on the strategies that Japanese decision makers could adopt. Findings – Japan does not share exactly the same rationales for adopting EMI as many European countries, however there is utility in looking to Europe for best practices. Japanese institutions of higher education can benefit from examining the linguistic, cultura...
The Relationship between Institutional Support and Campus Acceptance of Academic Service Learning

To understand how institutions are currently facilitating the service-learning movement, a survey was sent to 225 randomly selected colleges and universities with membership in their state campus compact organization. The survey data demonstrated a growing commitment in higher education to teaching and learning activities that extend the life of the campus into the greater community. Analysis of the data revealed the extent of the resources provided for service learning as well as the attitudes of faculty, students, and administrators toward a service-learning philosophy. Recommendations from the study regarding the implementation and promotion of service learning within campus communities are provided.
Detection of folliculostatin: A sensitive and specific bioassay using the female rat

To establish a sensitive and specific bioassay for the FSH-suppressing activity present in porcine follicular fluid (pFF), we examined the latency of pFF action when injected IV in the acutely ovariectomized (ovax) metestrous rat. By 2h post injection (5.5h after ovax), FSH was suppressed significantly in pFF vs. porcine serum-injected controls. LH was unaltered. In an experiment establishing a dose-response curve for pFF 4.5h after injection, 1.77 mg of pFF protein significantly suppressed FSH. The index of precision (-0.2188) and precision of slope (1.088) were well within acceptable limits for bioassays. We conclude that the ovax metestrous rat, injected 3.5h after surgery and sacrificed at 4.5 or 5.5h, is a sensitive and specific bioassay for folliculostatin.