cssi/SciSciGPT-SciSciNet huggingface dataset:
Magnetic susceptibility induced white matter MR signal frequency shifts--experimental comparison between Lorentzian sphere and generalized Lorentzian approaches.

Purpose The nature of the remarkable phase contrast in high-field gradient echo MRI studies of human brain is a subject of intense debates. The generalized Lorentzian approach (He and Yablonskiy, Proc Natl Acad Sci USA 2009;106:13558–13563) provides an explanation for the anisotropy of phase contrast, the near absence of phase contrast between white matter and cerebrospinal fluid, and changes of phase contrast in multiple sclerosis. In this study, we experimentally validate the generalized Lorentzian approach. Theory and Methods The Generalized Lorentzian Approach suggests that the local contribution to frequency shifts in white matter does not depend on the average tissue magnetic susceptibility (as suggested by Lorentzian sphere approximation), but on the distribution and symmetry of magnetic susceptibility inclusions at the cellular level. We use ex vivo rat optic nerve as a model system of highly organized cellular structure containing longitudinally arranged myelin and neurofilaments. The nerve's cylindrical shape allowed accurate measurement of its magnetic susceptibility and local frequency shifts. Results We found that the volume magnetic susceptibility difference between nerve and water is −0.116 ppm, and the magnetic susceptibilities of longitudinal components are −0.043 ppm in fresh nerve, and −0.020 ppm in fixed nerve. Conclusion The frequency shift observed in the optic nerve as a representative of white matter is consistent with generalized Lorentzian approach but inconsistent with Lorentzian sphere approximation. Magn Reson Med 71:1251–1263, 2014. © 2013 Wiley Periodicals, Inc.
Anterior Cruciate Ligament Allograft Surgery Underreporting of Graft Source, Graft Processing, and Donor Age

Background: There has been much controversy regarding the effects of sterilization techniques and graft history on the structural integrity of allograft ligaments used in reconstruction of the anterior cruciate ligament. The purpose of this review was to comprehensively examine anterior cruciate ligament allograft studies published in the last decade to evaluate the extent to which tissue source, tissue processing techniques, and donor age are reported.Methods: The authors reviewed 202 articles published from 1999 through November 2009, of which 68 retrospective, prospective, biomechanical, and histology studies evaluating 4689 allografts were included.Results: The majority of studies do not accurately report key elements of graft history including tissue bank, processing or sterilization technique, or donor age. Underreporting was particularly prominent in clinical studies as compared with basic science studies. Limited reporting of allograft processing, allograft source, and donor age raises serious que...
Guest Editorial Optics And Battlle

Colonel John Battelle was an early Ohio industrialist with major interests in the iron and steel industry and subsidiary interest in other metals. His son, Gordon Battelle, developed a consuming interest in industrial research mainly as a result of trying to recover zinc from ores for which the usual roasting process did not work. When Gordon Battelle died in 1923, he left his residual estate to the founding of an institute ". . . for the purpose of education in connection with the encouragement of creative and research work and the making of discoveries and inventions . . ." When his mother, Annie Norton Battelle, died in 1925, she left the bulk of her estate to the institute her son had founded. Battelle Memorial Institute opened its doors for business in 1929.
A Long‐Life Thermal Cell

Long life thermal cell using mixture of lithium chloride and potassium chloride as electrolyte
Aging Enhances Indirect Flight Muscle Fiber Performance yet Decreases Flight Ability in Drosophila

We investigated the effects of aging on Drosophila melanogaster indirect flight muscle from the whole organism to the actomyosin cross-bridge. Median-aged (49-day-old) flies were flight impaired, had normal myofilament number and packing, barely longer sarcomeres, and slight mitochondrial deterioration compared with young (3-day-old) flies. Old (56-day-old) flies were unable to beat their wings, had deteriorated ultrastructure with severe mitochondrial damage, and their skinned fibers failed to activate with calcium. Small-amplitude sinusoidal length perturbation analysis showed median-aged indirect flight muscle fibers developed greater than twice the isometric force and power output of young fibers, yet cross-bridge kinetics were similar. Large increases in elastic and viscous moduli amplitude under active, passive, and rigor conditions suggest that median-aged fibers become stiffer longitudinally. Small-angle x-ray diffraction indicates that myosin heads move increasingly toward the thin filament with age, accounting for the increased transverse stiffness via cross-bridge formation. We propose that the observed protein composition changes in the connecting filaments, which anchor the thick filaments to the Z-disk, produce compensatory increases in longitudinal stiffness, isometric tension, power and actomyosin interaction in aging indirect flight muscle. We also speculate that a lack of MgATP due to damaged mitochondria accounts for the decreased flight performance.
Genetic Variation In Vitro and In Vivo of an Attenuated Lassa Vaccine Candidate

The attenuated Lassa vaccine candidate ML29 is a laboratory-produced reassortant between Lassa and Mopeia viruses, two Old World arenaviruses that differ by 40% in nucleic acid sequence. In our previous studies, ML29 elicited sterilizing immunity against Lassa virus challenge in guinea pigs and marmosets and virus-specific cell-mediated immunity in both simian immunodeficiency virus (SIV)-infected and uninfected rhesus macaques. Here, we show that ML29 is stable after 12 passages in vitro without losing its plaque morphology or its attenuated phenotype in suckling mice. Additionally, we used deep sequencing to characterize the viral population comprising the original stock of ML29, the stock of ML29 after 12 passages in Vero cells, and the ML29 isolates obtained from vaccinated animals. Twenty-seven isolates bore approximately 77 mutations that exceeded 20% of the single-nucleotide polymorphism (SNP) changes at any single locus. Of these 77 mutations, 5 appeared to be host specific, for example, appearing in mice but not in primates. None of these mutations were reversions of ML29 to the sequences of the parental Lassa and Mopeia viruses. The host-specific mutations indicate viral adaptations to virus-host interactions, and such interactions make reasonable targets for antiviral approaches. Variants capable of chronic infection did not emerge from any of the primate infections, even in immune-deficient animals, indicating that the ML29 reassortant is reasonably stable in vivo. In conclusion, the preclinical studies of ML29 as a Lassa virus vaccine candidate have been advanced, showing high levels of protection in nonhuman primates and acceptable stability both in vitro and in vivo.
Medullary thyroid cancer: options for systemic therapy of metastatic disease?

Renato G. Martins, Division of Medical Oncology, Seattle Cancer Care Alliance, University of Washington, Seattle, WA Joseph G. Rajendran, Division of Nuclear Medicine, Seattle Cancer Care Alliance, University of Washington, Seattle, WA Peter Capell, Division of Endocrinology, Seattle Cancer Care Alliance, University of Washington, Seattle, WA David R. Byrd, Department of Surgery, Seattle Cancer Care Alliance, University of Washington, Seattle, WA David A. Mankoff, Divisions of Nuclear Medicine and Endocrinology, Seattle Cancer Care Alliance, University of Washington, Seattle, WA
Inhibition of Friend virus-induced splenomegaly by an associated lymphatic leukemia virus.

SummaryFriend virus was shown to be invariably associated with a virus that induces lymphatic leukemia. Prior inoculation with the latter inhibited Friend virus-induced reticulum cell proliferation in the spleen, but did not interfere with Friend virus replication. This effect was most marked when the interval between inoculation of the 2 viruses was 21 days.
Ultrafast Dynamics in DNA‐Mediated Electron Transfer: Base Gating and the Role of Temperature

The ultrafast dynamics of electron transfer (ET) between bases in DNA have been determined to elucidate the critical role of base-pair gating on the timescale of the electron transport and the temperature dependence of the rates. ET occurs only through DNA duplexes that adopt a specific, well-coupled alignment of bases (ET-active; see picture). Descriptions of ET dynamics must include fluctuations of DNA bases.
Reversal of Microvascular Rarefaction and Reduced Renal Mass Hypertension

This study examined the microcirculatory and renin-angiotensin system changes following the reversal of hypertension in reduced renal mass rats. Nine-week-old Sprague-Dawley reduced renal mass rats were placed on a low or high sodium diet for 4 or 8 weeks or a combination of 4 weeks of high sodium followed by 4 weeks of low sodium. Blood pressure was directly measured during the development of hypertension and its reversal. Plasma renin activity, angiotensin-converting enzyme activity, and angiotensin II concentrations were measured throughout the experiment. The cremaster and hindlimb muscles were removed, and microvascular density was determined by quantitative stereology. Four weeks of high sodium increased blood pressure (152+/-7 mm Hg) and reduced microvessel density (13.7%). Reduced renal mass hypertension was rapidly reversed after the rats were returned to a low sodium diet (124+/-7 mm Hg after 3 days), and microvascular density returned to control levels. After 4 weeks of high sodium, circulating plasma renin activity and angiotensin II fell by 94% and 82%, respectively. Plasma angiotensin-converting enzyme activity was increased after 2 weeks of high sodium but returned to control levels after 4 weeks of high sodium. This study demonstrates that microvascular density is reduced in reduced renal mass hypertensive rats following exposure to high sodium diet and this is associated with a fall in circulating plasma renin activity and angiotensin II levels. Microvascular density can return to normal levels after a reactivation of the circulating renin-angiotensin system. This study provides further evidence for the hypothesis that modulation of the renin-angiotensin system is important in the regulation of microvascular structure.
Improving the Performance of Multi-start Search on the Traveling Salesman Problem

Constructive multi-start search algorithms are commonly used to address combinatorial optimization problems. Multi-start algorithms recover from local optima by restarting, which can lead to redundant configurations when search paths converge. In this paper, we investigate ways to minimize redundancy using record keeping and analyze several restart algorithms in the context of iterative hill climbing with applications to the traveling salesman problem. Experimental results identify the best performing restart algorithms.
THE POSITIVE ACHIEVEMENTS OF ENDOCRINOLOGY

The recent appearance of a number of hypercritical articles on endocrinology tends to create a state of unwarranted skepticism toward this branch of medicine. So much stress has been laid upon the negative accomplishments that it is not amiss to present a brief review of its positive achievements. From the standpoint of the clinician all investigations center toward one object: progress in diagnosis and in therapy. While attending a large medical meeting recently, the writer was impressed by the negative tone that dominated most of the papers submitted. So much was said of what had not been accomplished and so little stress was laid upon what could be accomplished in therapy, that most of the physicians took back with them a mass of unknowns with which to combat their perplexing daily problems. It is distinctly desirable to maintain a critical attitude toward anything new in medicine, and such an attitude is an excellent balance to the unwarranted claims of many misguided enthusiasts.
Initiation of Apoptosis versus Necrosis by Photodynamic Therapy with Chloroaluminum Phthalocyanine

While chloroaluminum phthalocyanine is a highly effective photosensitizer of murine leukemia P388 or L1210 cells, the mode of cell death varies as a function of the PDT dose. When cells were incubated with 0.3 pit4 of the sensitizer, a light dose of 45 mJ cm-* (670 * 5 nm) yielded a 90% apoptotic cell population within 60 min. The sensitizer localized throughout the cytoplasm and catalyzed both lysosomal and mitochondria1 photodamage at this light dose. Higher light doses yielded progressively more membrane photodamage and inhibited the apoptotic response as determined by the examination of Hochst dye HO 33342-labeled nuclei, DNA fragmentation on gels and a poly(adenosy1ribose) polymerase (PARP)cleavage assay. Pulse-field gel electrophoresis revealed nonspecific DNA degradation to particles 30 kbp at the higher PDT doses but neither PARP cleavage nor apoptotic nuclei.
Parallel algorithms for simulating continuous time Markov chains

We have previously shown that the mathematical technique of uniformization can serve as the basis of synchronization for the parallel simulation of continuous-time Markov chains. This paper reviews the basic method and compares four different methods based on uniformization, evaluating their strengths and weaknesses as a function of problem characteristics. The methods vary in their use of optimism, logical aggregation, communication management, and adaptivity. Touchstone Delta multiprocessor, using up to 256 processors.
Spot Localization using PHY Layer Information

This paper explores the viability of precise indoor localization using physical layer information in WiFi systems. We find evidence that channel responses from multiple OFDM subcarriers can be a promising location signature. While these signatures certainly vary over time and environmental mobility, we notice that their core structure preserves certain properties that are amenable to localization. We attempt to harness these opportunities through a functional system called PinLoc, implemented on off-the-shelf Intel 5300 cards. We evaluate the system in a busy engineering building, a crowded student center, a cafeteria, and at the Duke University museum, and demonstrate localization accuracies in the granularity of 1m x 1m boxes, called “spots”. Results from 100 spots show that PinLoc is able to localize users to the correct spot with 89% mean accuracy, while incurring less than 6% false positives. We believe this is an important step forward, compared to the best indoor localization schemes of today, such as Horus.
The Effect of Consumership on Financial Satisfaction: Are “Good” Consumers More Satisfied?

A model of husband and wife financial satisfaction is developed, and related to consumership, a measure of behavioral performance. The model is tested for invariance over lower and higher income groups. The findings are that "good" consumers are more satisfied, and the marginal impact of increased consumer effort on financial satisfaction is approximately two times greater for the lower income group compared to the higher income group.
Insulin Resistance in Critically Injured Adults: Contribution of Pneumonia, Diabetes, Nutrition, and Acuity.

Abstract Purpose: Changes in insulin resistance (IR) cause stress-induced hyperglycemia after trauma, but the numerous factors involved in IR have not been delineated clearly. We hypothesized that a statistical model could help determine the relative contribution of different clinical co-variates to IR in critically injured patients. Patients and Methods: We retrospectively studied 726 critically injured patients managed with a computer-assisted glycemic protocol at an academic level I trauma center (639 ventilated controls without pneumonia (VWP) and 87 patients with ventilator-associated pneumonia (VAP). Linear regression using age, gender, body mass index (BMI), diabetes mellitus, pneumonia, and glycemic provision was used to estimate M, a marker of IR that incorporates both the serum blood glucose concentration (BG) and insulin dose. Results: Increasing M (p < 0.001) was associated with age (1.62%; 95% confidence interval [CI] 1.27%–1.97% per decade), male gender (9.78%; 95% CI 8.28%–12.6%), BMI (4.32...
Active Writing (essay #2)

This is the second in a series of short, entertaining essays I've written about specific legal writing skills. This essay is about creating active-sounding verbs. It first examines the passive voice, discussing both its shortcomings and the circumstances under which it is appropriate. An example of the former is when the passive voice masks the identity of the subject, as in the Aesop Fable in which a young mouse suggests that a bell "be hung" around a cat's neck. An example of the latter is when the result of the action is more important than the identity of the actor, as in Grandma got [sic] run over by a reindeer. The essay then examines nominalizations. Nominalizations are words in drag: they are verbs or adjectives that masquerade, ostentatiously though unconvincingly, as nouns. The essay describes the shortcomings of nominalizations and also how to spot and correct them.
Predictors of Postoperative Seizure Recurrence: A Longitudinal Study of Temporal and Extratemporal Resections

Objective. We investigated the longitudinal outcome of resective epilepsy surgery to identify the predictors of seizure recurrence. Materials and Methods. We retrospectively analyzed patients who underwent resections for intractable epilepsy over a period of 7 years. Multiple variables were investigated as potential predictors of seizure recurrence. The time to first postoperative seizure was evaluated using survival analysis and univariate analysis at annual intervals. Results. Among 70 patients, 54 (77%) had temporal and 16 (23%) had extratemporal resections. At last follow-up (mean 48 months; range 24–87 months), the outcome was Engel class I in 84% ( ) of patients. Seizure recurrence followed two patterns: recurrence was “early” (within 2 years) in 82% of patients, of whom 83% continued to have seizures despite optimum medical therapy; recurrence was “late” (after 2 years) in 18%, of whom 25% continued to have seizures subsequently. Among the variables of interest, only resection site and ictal EEG remained as independent predictors of seizure recurrence over the long term ( ). Extratemporal resection and discordance between ictal EEG and resection area were associated with 4.2-fold and 5.6-fold higher risk of seizure recurrence, respectively. Conclusions. Extratemporal epilepsy and uncertainty in ictal EEG localization are independent predictors of unfavorable outcome. Seizure recurrence within two years of surgery indicates poor long-term outcome.
Heterogeneity in the Small-Scale Deformation Behavior of Disordered Nanoparticle Packings

Atomic force microscopy-based nanoindentation is used to image and probe the local mechanical properties of thin disordered nanoparticle packings. The probed region is limited to the size of a few particles, and an individual particle can be loaded and displaced to a fraction of a single particle radius. The results demonstrate heterogeneous mechanical response that is location-dependent. The weak locations may be analogous to the “soft spots” previously predicted in glasses and other disordered packings.
5′ and 3′ Untranslated Regions Strongly Enhance Performance of Geminiviral Replicons in Nicotiana benthamiana Leaves

We previously reported a recombinant protein production system based on a geminivirus replicon that yields high levels of vaccine antigens and monoclonal antibodies in plants. The bean yellow dwarf virus (BeYDV) replicon generates massive amounts of DNA copies, which engage the plant transcription machinery. However, we noticed a disparity between transcript level and protein production, suggesting that mRNAs could be more efficiently utilized. In this study, we systematically evaluated genetic elements from human, viral, and plant sources for their potential to improve the BeYDV system. The tobacco extensin terminator enhanced transcript accumulation and protein production compared to other commonly used terminators, indicating that efficient transcript processing plays an important role in recombinant protein production. Evaluation of human-derived 5’ untranslated regions (UTRs) indicated that many provided high levels of protein production, supporting their cross-kingdom function. Among the viral 5’ UTRs tested, we found the greatest enhancement with the tobacco mosaic virus omega leader. An analysis of the 5’ UTRs from the Arabidopsis thaliana and Nicotinana benthamiana photosystem I K genes found that they were highly active when truncated to include only the near upstream region, providing a dramatic enhancement of transgene production that exceeded that of the tobacco mosaic virus omega leader. The tobacco Rb7 matrix attachment region (MAR) inserted downstream from the gene of interest provided significant enhancement, which was correlated with a reduction in plant cell death. Evaluation of agrobacterium strains found that EHA105 enhanced protein production and reduced cell death compared to LBA4301 and GV3101. We used these improvements to produce Norwalk virus capsid protein at >20% total soluble protein, corresponding to 1.8mg/g leaf fresh weight, more than twice the highest level ever reported in a plant system. We also produced the monoclonal antibody rituximab at 1mg/g leaf fresh weight.
Immersions in Global Equality and Social Justice: A Model of Change

Part of the Adult and Continuing Education and Teaching Commons, Business Law, Public Responsibility, and Ethics Commons, Civic and Community Engagement Commons, Communitybased Learning Commons, Community-based Research Commons, Curriculum and Social Inquiry Commons, Developmental Psychology Commons, Educational Administration and Supervision Commons, Educational Assessment, Evaluation, and Research Commons, Educational Leadership Commons, Educational Methods Commons, Higher Education Commons, Higher Education and Teaching Commons, International and Area Studies Commons, Leadership Studies Commons, Liberal Studies Commons, Multicultural Psychology Commons, Nonprofit Administration and Management Commons, Race, Ethnicity and Post-Colonial Studies Commons, Service Learning Commons, Social and Philosophical Foundations of Education Commons, Social Work Commons, and the Student Counseling and Personnel Services Commons
Toward a Functional Definition of Methane Super-Emitters: Application to Natural Gas Production Sites.

Emissions from natural gas production sites are characterized by skewed distributions, where a small percentage of sites—commonly labeled super-emitters—account for a majority of emissions. A better characterization of super-emitters is needed to operationalize ways to identify them and reduce emissions. We designed a conceptual framework that functionally defines superemitting sites as those with the highest proportional loss rates (methane emitted relative to methane produced). Using this concept, we estimated total methane emissions from natural gas production sites in the Barnett Shale; functionally superemitting sites accounted for roughly three-fourths of total emissions. We discuss the potential to reduce emissions from these sites, under the assumption that sites with high proportional loss rates have excess emissions resulting from abnormal or otherwise avoidable operating conditions, such as malfunctioning equipment. Because the population of functionally superemitting sites is not expected to b...
Regional white matter development in very preterm infants: perinatal predictors and early developmental outcomes.

BACKGROUND Preterm infants are at risk for white matter (WM) injury and adverse neurodevelopmental outcomes. METHODS Serial diffusion tensor magnetic resonance imaging data were obtained from very preterm infants (N = 78) born <30 wk gestation imaged up to four times from 26-42 wk postmenstrual age. Slopes were calculated for fractional anisotropy (FA) and mean diffusivity (MD) within regions of interest for infants with ≥2 scans (N = 50). Sixty-five children underwent neurodevelopmental testing at 2 y of age. RESULTS FA slope for the posterior limb of the internal capsule was greater than other regions. The anterior limb of the internal capsule (ALIC), corpus callosum, and optic radiations demonstrated greater FA slope with increasing gestational age. Infants with patent ductus arteriosus had lower FA slope in the ALIC. MD slope was lower with prolonged ventilation or lack of antenatal steroids. At 2 y of age, lower motor scores were associated with lower FA in the left but higher FA in the right inferior temporal lobe at term-equivalent age. Better social-emotional competence was related to lower FA in the left cingulum bundle. CONCLUSION This study demonstrates regional variability in the susceptibility/sensitivity of WM maturation to perinatal factors and relationships between altered diffusion measures and developmental outcomes in preterm neonates.
Thunderclap Headache Secondary to Pneumocephalus Following Epidural Anesthesia.

A 33-year-old woman presented in labor at 41 weeks of gestation. She received epidural anesthesia and developed a thunderclap headache immediately after the injection. The pain was of sudden onset, described as 10 of 10 in intensity and pressure in quality. It was the “worst headache” of her life. It was located in the top of the head and radiated to the right side when she laid on her left. There was no associated nausea, emesis, photophobia, phonophobia, visual changes, or other neurologic symptoms. Neurologic examination was normal. An emergent noncontrast computed tomography of the head showed extensive pneumocephalus without other abnormalities (Figure 1). The patient was treated with butorphanol with significant improvement in pain. She was able to deliver a healthy newborn, and the headache resolved by the next morning. Figure 1. Noncontrast computed tomography of the head at the level of the basal nuclei (left) and midbrain (right) demonstrates extensive supra and infratentorial pneumocephalus. Both abrupt onset and a new headache during pregnancy are considered red flags for secondary headache disorders.1 Potential causes in this scenario include subarachnoid hemorrhage, cerebral vein thrombosis, pituitary apoplexy, and posterior reversible encephalopathy syndrome.2 Headache can rarely occur after epidural anesthesia, and it is often attributed to intracranial hypotension due to leakage of cerebrospinal fluid.3 Although the incidence of pneumocephalus after epidural anesthesia is unknown, it seems to be a very rare complication, as the available evidence is limited to case reports.4,5 Pneumocephalus should be considered as a cause of secondary headache in pregnancy, particularly if pain develops immediately after epidural anesthesia. In most patients, the headache resolves with conservative measures.
Political Natality: The Rebirth of Beginning

The category of natality includes a preliminary manifestation at birth — the premiere of a new creation and the capacity for beginning which is announced by the birth of a child. The coincidence of the beginner and a beginning is the meaning we assigned to primary natality; its factual content was given by the experiences of play and education by which the beginner experimented with the faculty for novelty as the capacity to commence projects and to insert unique interpretations in the world of the nursery. These nursery experiences of play and education were shown to be activities of a pre-political kind inasmuch as through them children were introduced to and prepared for the world of adulthood rather than the world of politics. Politics, to be sure, is not like the nursery and this for the most obvious of reasons: children are peers only to other children; they are still under the guidance of adult authority; the principle of political equality does not govern their relationships; the world of childhood is essentially private and self- contained; childhood interests and activities are not usually inspired by a comprehensive love and reverence for the world of human affairs. Politics is not like the nursery because in politics the principles of equality, distinctness and the attitude of amor mundi reign supreme and become the possibilities for those adults who partake of the political in a mature and responsible manner.
Modern Protective Structures

In today's world, reasonably predictable military operations have been replaced by low intensity conflicts-less predictable terrorist activities carried out by determined individuals or small groups that possess a wide range of backgrounds and capabilities. Because of the threats posed by this evolving type of warfare, civil engineers and emergency
Exploring role dialectics in inter-service admission handoffs: a qualitative analysis of physician communication

ABSTRACTAdmission handoffs between emergency physicians (EPs) and internal medicine/hospitalist physicians (IMHPs), a frequently occurring form of patient transfer, remain understudied despite their importance to care continuity. Handoffs function as more than simple information transfer; they require a repertoire of interpersonal skills to accomplish tasks and develop professional relationships. Relational Dialectics Theory (RDT), a perspective that asserts social life consists of oppositional and unified discourses present in personal relationships, frames the current study. We use role dialectics to more fully understand the contradictions that emerge from the competing discourses of physician roles. Data were collected from six focus groups consisting of residents and attending physicians working at a large, urban, academic medical center in the Midwest United States. Using a grounded, constant-comparative approach, analysis of transcripts reveals that these physicians encounter two key role dialectic...
Immuno-affinity Capture Followed by TMPP N-Terminus Tagging to Study Catabolism of Therapeutic Proteins.

Characterization of in vitro and in vivo catabolism of therapeutic proteins has increasingly become an integral part of discovery and development process for novel proteins. Unambiguous and efficient identification of catabolites can not only facilitate accurate understanding of pharmacokinetic profiles of drug candidates, but also enables follow up protein engineering to generate more catabolically stable molecules with improved properties (pharmacokinetics and pharmacodynamics). Immunoaffinity capture (IC) followed by top-down intact protein analysis using either matrix-assisted laser desorption/ionization or electrospray ionization mass spectrometry analysis have been the primary methods of choice for catabolite identification. However, the sensitivity and efficiency of these methods is not always sufficient for characterization of novel proteins from complex biomatrices such as plasma or serum. In this study a novel bottom-up targeted protein workflow was optimized for analysis of proteolytic degradat...
Lead and Mg isotopic age constraints on the evolution of the HED parent body

The large collection of howardite-eucrite-diogenite (HED) meteorites allows us to study the initial magmatic differentiation of a planetesimal. We report Pb-Pb ages of the unequilibrated North West Africa (NWA) 4215 and Dhofar 700 diogenite meteorites and their mass-independent 26Mg isotope compositions (26Mg*) to better understand the timing of differentiation and crystallization of their source reservoir(s). NWA 4215 defines a Pb-Pb age of 4484.5 ± 7.9 Myr and has a 26Mg* excess of +2.3 ± 1.6 ppm whereas Dhofar 700 has a Pb-Pb age of 4546.4 ± 4.7 Myr and a 26Mg* excess of +25.5 ± 1.9 ppm. We interpret the young age of NWA 4215 as a thermal overprint, but the age of Dhofar 700 is interpreted to represent a primary crystallization age. Combining our new data with published Mg isotope and trace element data suggests that approximately half of the diogenites for which such data are available crystallized within the first 1–2 Myr of our solar system, consistent with a short-lived, early-formed magma ocean undergoing convective cooling. The other half of the diogenites, including both NWA 4215 and Dhofar 700, are best explained by their crystallization in slowly cooled isolated magma chambers lasting over at least ~20 Myr.
Quantum imaging and spatial entanglement characterization with an EMCCD camera

We utilize a single-photon sensitive electron multiplying CCD camera as a massively parallel coincidence counting apparatus to study spatial entanglement of photon pairs. This allows rapid measurement of transverse spatial entanglement in a fraction of the time required with traditional point-scanning techniques. We apply this technique to quantum experiments on entangled photon pairs: characterization of the evolution of entanglement upon propagation, and measurement of one- and two-photon portions of the state transmitted through non-unitary (lossy) objects, and quantum phase imaging.
Treating the chronic-phase chronic myeloid leukemia patient: which TKI, when to switch and when to stop?

ABSTRACTIntroduction: With the discovery of imatinib mesylate nearly 20 years ago, tyrosine kinase inhibitors (TKIs) were found to be effective in chronic myeloid leukemia (CML). TKI therapy has since revolutionized the treatment of CML and has served as a paradigm of success for targeted drug therapy in cancer. Several new TKIs for CML have been approved over the last two decades that exhibit improved potency over imatinib and have different off-target profiles, providing options for individualized therapy selection.Areas covered: Current management of chronic phase CML, including guidance on the sequential use of imatinib and newer-generation TKIs and evolving treatment strategies such as TKI discontinuation. Relevant literature was identified by searching biomedical databases (i.e. PubMed) for primary research material.Expert commentary: Although survival outcomes have drastically improved for CML patients, treatment for CML has grown more complex with the introduction of next-generation TKIs and the a...
Wrinkles in the Administrative Fabric: Regulatory Initiatives and California Economic Development

This article first examines legal issues surrounding California’s decision to enact by regulation and provide a feed-in tariff for certain renewable power less than a decade after the economic collapse of California’s new system of electric sector regulation in 2001. Second, the article also examines legal issues surrounding the ethanol/liquid fuels program implemented as part of California climate change regulation. These two seminal administrative law cases construe the flexibility and limits of state regulation of in-state electricity transactions and out-of-state liquid fuels destined to be sold in the state. Both of these significant California administrative law programs were challenged legally, as violations of both state administrative law and violations of the federal Constitution. This article examines these and other state administrative law legal issues and challenges.
Gene therapy for age-related macular degeneration

In neovascular age related macular degeneration (nAMD), gene therapy to chronically express anti-vascular endothelial growth factor (VEGF) proteins could ameliorate the treatment burden of chronic intravitreal therapy and improve limited visual outcomes associated with 'real world' undertreatment. Areas covered: In this review, the authors assess the evolution of gene therapy for AMD. Adeno-associated virus (AAV) vectors can transduce retinal pigment epithelium; one such early application was a phase I trial of AAV2-delivered pigment epithelium derived factor gene in advanced nAMD. Subsequently, gene therapy for AMD shifted to the investigation of soluble fms-like tyrosine kinase-1 (sFLT-1), an endogenously expressed VEGF inhibitor, binding and neutralizing VEGF-A. After some disappointing results, research has centered on novel vectors, including optimized AAV2, AAV8 and lentivirus, as well as genes encoding other anti-angiogenic proteins, including ranibizumab, aflibercept, angiostatin and endostatin. Also, gene therapy targeting the complement system is being investigated for geographic atrophy due to non-neovascular AMD. Expert opinion: The success of gene therapy for AMD will depend on the selection of the most appropriate therapeutic protein and its level of chronic expression. Future investigations will center on optimizing vector, promoter and delivery methods, and evaluating the risks of the chronic expression of anti-angiogenic or anti-complement proteins.
Abstract 4737: A lung cancer risk classifier comprising genome maintenance genes measured in normal bronchial epithelial cells

Background: Annual low dose CT (LDCT) screening of individuals at high demographic risk reduces lung cancer mortality by more than 20%. However, subjects selected for screening based on demographic criteria typically have less than a 10% lifetime risk for lung cancer. Thus, there is need for a biomarker that better stratifies subjects for LDCT screening. Toward this goal, we previously reported a lung cancer risk test (LCRT) biomarker comprising 14 genome-maintenance (GM) pathway genes measured in normal bronchial epithelial cells (NBEC) that accurately classified cancer (CA) from non-cancer (NC) subjects. The primary goal of the studies reported here was to optimize the LCRT biomarker for high specificity and ease of clinical implementation. Methods: Targeted competitive multiplex PCR amplicon libraries were prepared for next generation sequencing (NGS) analysis of transcript abundance at 68 sites among 33 GM target genes in NBEC specimens collected from a retrospective cohort of 120 subjects, including 60 CA cases and 60 NC controls. Genes were selected for analysis based on contribution to the previously reported LCRT biomarker and/or prior evidence for association with lung cancer risk. Linear discriminant analysis was used to identify the most accurate classifier suitable to stratify subjects for screening. Results: The best classifier comprised 11 features including age and 10 transcript abundance assays representing nine genes; specifically, CDKN1A, E2F1, ERCC5, GPX1, GSTP1, KEAP1, TP63, XPA, and XRCC1. After cross-validation, the Receiver Operator Characteristic area under the curve was 0.94 (95% CI: 0.92-0.96) and overall classification accuracy was 88.3% (95% CI 82.4%-94.1%). Using a threshold set at 95% sensitivity, specificity was > 70%. Conclusions: The LCRT biomarker reported here displayed high specificity and ease of implementation on a high throughput, quality-controlled targeted NGS platform. As such, it is optimized for clinical validation in specimens from the ongoing LCRT blinded prospective cohort study. Following validation, the biomarker is expected to have clinical utility by better stratifying subjects for annual lung cancer screening compared to current demographic criteria alone. Citation Format: Jiyoun Yeo, Erin Crawford, Xiaolu Zhang, Sadik Khuder, Tian Chen, Albert Levin, Thomas Blomquist, James Willey. A lung cancer risk classifier comprising genome maintenance genes measured in normal bronchial epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4737. doi:10.1158/1538-7445.AM2017-4737
Kinetics of SHS reactions: A review

The current state of chemical kinetics for self-propagating high-temperature non-catalytic reactions has been reviewed for results over the past 50 years. Five different characterization techniques are primarily considered: differential thermal analysis (DTA), electrothermal explosion (ETE), electrothermography (ET), combustion velocity/temperature analyses (Merzhanov–Khaikin and Boddington–Laye approaches), and other advanced in-situ diagnostics, including time-resolved X-ray diffraction (TRXRD). Based on the summary of results thus far, recommendations are given for the future of SHS kinetic research.
Thermotropic Polyethers and Copolyethers: A New Class of Main Chain Liquid Crystalline Polymers

In 1975 deGennes suggested that thermotropic liquid crystalline (LC) main chain polymers might be prepared by incorporating mesogenic and flexible segments in the polymer main chain repeating units.1 In the same year, Roviello and Sirigu provided the first example of thermotropic LC main chain polymers, i.e., poly-alcanoates of p,p′-hydroxy-α,α′-dimethyl benzalazine.2 Since then, several research groups have become actively engaged in the study of thermotropic LC main chain polymers. This new field of polymer chemistry has been recently reviewed.3
Relative Reactivity of Hydroxyl Groups in Monosaccharides

The furanoid and pyranoid cyclic structures of monosaccharides generally may have four types of chemically distinguishable hydroxyl groups: (1) the anomeric (hemiacetal, lactol) hydroxyl group and (2) three types of alcoholic hydroxyl groups: (a) the primary hydroxyl group, which is always exocyclic with regard to the carbohydrate ring and is found in both hexopyranoses and pento- or hexofuranoses, (b) the endocyclic secondary hydroxyl groups found in both hexopyranoses and pento- or hexofuranoses, and (c) the exocyclic secondary hydroxyl groups found in hexofuranoses or in higher sugars containing hexopyranose ring.
Drug Abuse and Convulsive States

With the exception of alcohol, the influence of psychoactive drugs on epileptic patients does not seem to have undergone systematic examination. Yet this information is of considerable importance to the drug counselor since drugs, particularly in combination with other physical factors which increase seizure frequency, can interfere with the subject’s ability to hold a job or, in some cases, even to be able to maintain normal social relationships. This, in turn, may result in more extensive drug abuse and ultimate socio-psychological deterioration.
Peripheral Inflammation Accelerates the Onset of Mechanical Hypersensitivity after Spinal Cord Injury and Engages Tumor Necrosis Factor α Signaling Mechanisms.

Abstract Previously, we showed that noxious stimulation of the tail produces numerous detrimental effects after spinal cord injury (SCI), including an earlier onset and increased magnitude of mecha...
Examining Public Communication About Kidney Cancer on Twitter

PURPOSESeveral studies have described the content of Twitter conversations about lung, breast, and prostate cancer, but little is known about how the public uses Twitter to discuss kidney cancer. W...
Ventilation and Indoor Air Quality in New California Homes with Gas Appliances and Mechanical Ventilation

Author(s): Kim, Yang; Less, Brennen; Singer, Brett; Chan, Wanyu R; Walker, Iain | Abstract: Substantial energy is used to condition the air that enters California homes through leaks in the building envelope and ductwork - typically about a third of all heating and cooling. Reducing this through air sealing is essential to California achieving zero energy homes. However, this outdoor air also dilutes pollutants emitted inside homes and contributes to a healthy indoor environment and acceptable indoor air quality (IAQ). To address this IAQ issue, California’s Title 24 Building Standards have required mechanical ventilation in new homes since 2008. This report presents a comprehensive study of the impacts of these requirements in recently constructed homes with natural gas appliances. The study included a survey about satisfaction and activities that impact IAQ; a field study of homes built to 2008 or later; and simulations assessing how various ventilation rates would impact chronic exposures to an indoor emitted pollutant as air tightness improves in California. The report focuses on the field study; the webbased survey and simulation elements are described in appendices. The field study characterized 70 homes built between 2011 and 2017. Each home was monitored over roughly one week with the dwelling unit mechanical ventilation system operating and windows closed. Pollutant measurements included time-resolved fine particulate matter (PM2.5) indoors and outdoors, and formaldehyde, nitrogen dioxide (NO2), and carbon dioxide (CO2) indoors. Time-integrated measurements were made for formaldehyde, NO2 and nitrogen oxides (NOX) indoors and outdoors at all homes. Activity monitoring devices were installed on the cooktop, range hood and other exhaust fans, and the heating and cooling system. The field study found that most homes met most ventilation requirements and the dwelling unit ventilation fans on average moved 50% more airflow than the minimum specified in Title 24. Air pollutant concentrations were similar or lower than those reported in a study of recent construction California new homes conducted in 2007-08. Notably, the median formaldehyde level was 38% lower than in the prior study. Measured concentrations were below health guidelines for most pollutants, indicating that IAQ is acceptable in new California homes when dwelling unit mechanical ventilation is used. However, the dwelling unit mechanical ventilation fans were only operating in one quarter of the homes when first visited and the control switches in many homes did not have informative labels as required by the standards. Corrective action needs to be taken to improve labeling and controls for ventilation systems.
A Longitudinal Ambulatory Quality Improvement Curriculum That Aligns Resident Education With Patient Outcomes: A 3-Year Experience:

Quality improvement (QI) plays a vital role in practice management, patient care, and reimbursement. The authors implemented a 3-year longitudinal curriculum that combined QI didactics, intervention development, and implementation at university-based, community-based, and Veterans Administration-based practices. Highlights included Plan-Do-Study-Act cycle format, team-based collaboration to brainstorm interventions, interdisciplinary QI council to select and plan interventions, system-wide intervention implementation across entire clinic populations with outcome monitoring, and intervention modifications based on challenges. A pre-post survey assessed residents' confidence in QI skills and interdisciplinary team participation, while quarterly quality data assessed patient outcomes. All 150 internal medicine residents participated. Confidence in QI and interdisciplinary team participation improved significantly (P < .001). Patient outcomes improved for 6 of 9 targeted projects and were sustained at 1 year. This curriculum is a systems-based innovation designed to improve patient care and encourage interdisciplinary teamwork and can be adopted by residencies seeking to improve engagement in QI.
On Pellegrino and Thomasma’s Admission of a Dilemma and Inconsistency

Edmund Pellegrino and David Thomasma's writings have had a worldwide impact on discourse about the philosophy of medicine, professionalism, bioethics, healthcare ethics, and patients' rights. Given their works' importance, it is surprising that commentators have ignored their admission of an unresolved and troubling dilemma and inconsistency in their theory. The purpose of this article is to identify and state what problems worried them and to consider possible solutions. It is argued that their dilemma stems from their concerns about how to justify professional rules restricting colleagues from performing acts they view as direct, active, and formal (intentional) killings, such as physician-assisted suicide, mercy killing, and abortion. It is further argued that their inconsistency is that they both assert and deny that professional colleagues should not use their moral or theological values to impose professional restrictions on other colleagues without adequate philosophical grounds. At risk are their arguments about the nature of an internal morality for medicine, a secular and multicultural basis for medical ethics, and a nonarbitrary way to determine what acts fall outside the ends of medicine. These are arguments they claim also apply to other healthcare professions. The article begins with a brief overview of their key positions to provide the context in which they make their admission.