cssi/SciSciGPT-SciSciNet huggingface dataset:
D-cycloserine-Naloxone interactions in opioid-dependent humans under a novel-response naloxone discrimination procedure.

Six participants currently in opioid maintenance treatment were trained to distinguish between naloxone (0.15 mg/70 kg, intramuscularly [i.m.]) and placebo under an instructed novel-response drug-discrimination procedure. Doses of the partial glycine agonist D-cycloserine (0-500 mg/70 kg, per os [P.O.]) alone and combined with naloxone (0.15 mg/70 kg) were then tested. D-cycloserine alone produced minimal drug-appropriate responding, no significant changes in self-reported effects, and increases only in systolic blood pressure. When combined with the naloxone, D-cycloserine partially attenuated naloxone-appropriate responding. D-cycloserine attenuated naloxone-induced increases in visual analog scale ratings of "like naloxone" and scores on the Lysergic Acid Diethyl Amide subscale of the Addiction Research Center Inventory (D. R. Jasinski, 1977; W. R. Martin, J. W. Sloan, J. D. Sapiro, & D. R. Jasinski, 1971). Naloxone attenuated D-cycloserine-induced increases in systolic blood pressure. These results suggest that D-cycloserine at doses up to 500 mg/70 kg may have some limited usefulness in relieving symptoms of opioid withdrawal.
PERCUTANEOUS ABSORPTION OF METHOTREXATE AS ITS SODIUM SALT IN VIVO

AbstractThe percutaneous absorption of methotrexate as its sodium salt has been demonstrated in vivo using the hairless mouse as an experimental model. Following topical administration of 0.2 mg sodium methotrexate in concentrated aqueous solution, drug concentrations were measured in plasma at 3, 4, 5, 6, and 8 hrs. Methotrexate was not detected in plasma at 3 hrs, but it was found in pharmacologically significant mean concentrations for the remainder of the study (/μmol/L): 4 hrs, 0.13; 5 hrs, 0.38; 6 hrs, 1.01; and 8 hrs, 0.23. These findings suggest that percutaneous absorption of methotrexate does occur and that individuals handling the drug should take appropriate precautions. Biological monitoring may also be indicated for such persons.
Cooperative Learning through Team-Based Projects in the Biotechnology Industry

We have developed a cooperative-learning, case studies project model that has teams of students working with biotechnology professionals on company-specific problems. These semester-long, team-based projects can be used effectively to provide students with valuable skills in an industry environment and experience addressing real issues faced by biotechnology companies. Using peer-evaluations, we have seen improvement in students’ professional skills such as time-management, quality of work, and level of contribution over multiple semesters. This model of team-based, industry-sponsored projects could be implemented in other college and university courses/programs to promote professional skills and expose students to an industry setting.
Automated bi-objective design optimization of multi-MW direct-drive PM machines using CE-FEA and differential evolution

Design optimization of a multi-MW direct-drive PMAC machine based on computationally efficient-FEA (CE-FEA) and multi-objective differential evolution (DE) algorithm is presented in this paper. The CE-FEA based models allow ultra-fast analysis and design of synchronous electric machinery. In this work, a DE algorithm is used to vary a large number of stator and rotor parameters to optimize multiple objectives, such as average torque, efficiency, the cogging and the ripple torques that are evaluated using CE-FEA. The method is demonstrated on a motor for a direct-drive rated at 20 MW and 150 r/min. The following four case-study machines are optimized: 1) fractional-slot embedded surface-PM, 2) fractional-slot interior-PM, 3) integer-slot embedded surface-PM, and 4) integer-slot interior-PM. Design optimization of interior-PM machines includes an additional search for an optimum operating torque angle corresponding to the maximum torque per ampere (MTPA) condition.
Identification of youth psychosocial problems during pediatric primary care visits

This investigation applied the Gateway Provider Model (GPM) of child mental health services to investigate whether characteristics of the child, family, visit, and provider were related to the identification of youth psychosocial problems during primary care visits. Data were gathered during 774 visits to 54 primary care providers (PCPs) at 13 clinics. Similar to previous investigations in primary care settings, 42% of youth demonstrated at least a sub-threshold clinical mental health problem. Most PCPs reported high job satisfaction and control, but reported varying access to mental health specialists. PCPs generally had positive attitudes and beliefs about treating psychosocial problems but many reported that doing so was burdensome. Identification was more likely when the visit was for a mental health problem, when issues related to psychosocial problems were discussed during the visit, when the youth demonstrated mental health symptoms, impairment, or burden to the family, and when the youth was older, uninsured, or received Medicaid. Identification was less likely when the PCP reported greater burden associated with treating psychosocial problems and when the PCP reported greater accessibility to mental health specialists. These results suggest that identification is associated with the interaction of multilevel factors and that the GPM is a useful model to investigate points of intervention for improving the identification of children’s mental health problems in primary care settings.
Collagen-based fiber-gel constructs engineered for schwann cell guidance and adult axon growth

Adult Schwann cells cultured within three-dimensional (3D) collagen-based nervous tissue constructs demonstrated downstream migration and potential use in the contact-guidance of regenerating adult dorsal root ganglia (DRG) axons. Type I collagen extracted from rat tail tendons was used to prepare collagen dispersions for wet spinning micron-size collagen fibers. Biodegradable poly-L-lactic acid (PLLA) and wet-spun collagen fibers containing various extracellular matrix (ECM) proteins were used to evaluate Schwann cell guidance and survival of primary adult rat DRGs, which presents a more realistic model for studying regenerative processes.
A low-power microprocessor for data-driven analysis of analytically-intractable physiological signals in advanced medical sensors

Data-driven methods based on machine learning enable powerful frameworks for analyzing complex physiological signals in medical-sensor applications; however, these methods are not well supported by traditional DSPs. A general-purpose microprocessor is presented in 130nm CMOS that integrates configurable accelerators, enabling low-energy hardware to support the broadest range of machine-learning frameworks reported to date. In addition to computational energy, memory limitations due to the high-order data-driven models are overcome by an embedded compression/decompression accelerator, which reduces the memory footprint by 4× with overhead <;8%. Using six medical applications with real clinical data, overall energy savings of 3.1-497× are demonstrated with the accelerator-based architecture.
Free Histidine in Cloacal Waste from Newly Hatched Chicks and its Relationship to Avian Lymphomatosis

Abstract AN INVESTIGATION of free amino acids in chickens using paper chromatography has been published by Chubb (1959). The amino acids reported in his work were found in the urine, blood and body tissues of normal birds. However, there is no information regarding free amino acids found in chickens and their relationship to avian lymphomatosis. This paper reports chromatographic investigations of the free amino acids in the cloacal waste from newly hatched unfed chicks. Throughout the investigations, all free amino acids were examined for a correlation between their occurrence and subsequent occurrence of avian lympho-matosis. It became apparent that only histidine exhibited this correlation. EXPERIMENTAL Samples of cloacal waste were collected from newly hatched, unfed chicks evacuated within five hours after removal from hatching trays. The excrement was collected in individual test tubes and only the samples from female chicks were used unless otherwise noted. Ethyl alcohol was added to the…
Glycosyl acceptors in intact and permeabilized normal and cystic fibrosis fibroblasts

Using cell permeabilization, a technique which allows addition of exogenously supplied radiolabeled sugar nucleotides to serve as direct glycosyl donors, oligosaccharide biosynthesis was examined in fibroblasts obtained from normal and cystic fibrosis (CF) subjects. Incubation of logarithmically growing cells with either radiolabeled leucine or xylose has indicated that there was a difference in the synthetic rate between the cell types. Protein synthesis in normal cells made permeable with 50 micrograms/ml lysolecithin (LL) was demonstrated to be absent, and could not be induced to take place by adding exogenous components, including energy sources and amino acids, normally required for protein synthesis. Thus radiolabeled sugars were being added to peptide acceptors which were already present at the time of LL addition. Both permeable and intact fibroblasts were exposed to labeled UDP-xylose, UDP-galactose, and UDP-glucuronic acid, all donors of mucopolysaccharide precursors. The uptake of xylose into protein was the same for both normal and CF cells, but permeable CF fibroblasts incorporated statistically greater amounts of sugar from UDP-galactose and UDP-glucuronic acid. Intact CF cells were also labeled using these two sugar nucleotides. Trypan blue exclusion indicated CF and normal fibroblasts were equally intact. This and the fact that preincubation of CF cells with the appropriate cold sugar nucleotide eliminated the differences in incorporation between the normal and CF cells suggested that CF fibroblasts had more cell surface acceptor than the normal cells.
Narrative, Free Space, and Political Leadership in Social Movements

Interviews with leaders of civil rights efforts in four rural communities in the South suggest how narratives nurture political resistance among repressed and subordinated groups. Narratives provide group members historical precedents of individual and collective resistance, an alternative explanation of the group's condition, and an exposition of the virtues of a group that others consider virtueless. This discussion of narratives permits us to understand them as a formative element of local leadership and as an explicitly political element of social movements. This discussion also permits us to interpret social movements as a set of related local efforts of resistance and in terms of the spaces in which narratives occur.
FISH PREDATION OF ZEBRA MUSSELS ATTACHED TO QUADRULA QUADRULA (BIVALVIA: UNIONIDAE) AND BENTHIC MOLLUSCS IN A GREAT LAKES COASTAL WETLAND

Although the introduced zebra mussel, Dreissena polymorpha, has eliminated most native unionid populations within the lower Great Lakes, some recent surveys have found diverse unionid communities in several Lake Erie coastal wetlands. In 2004, we tested whether fish predators reduced zebra mussels on Quadrula quadrula (Unionidae) in a Lake Erie coastal wetland. In June, we placed unionids and colonization plates in small-mesh exclosures (2.5-cm × 2.5-cm mesh), large-mesh exclosures (5-cm × 10-cm mesh), and open exclosures (2.5-cm × 2.5-cm mesh with two 40-cm × 40-cm openings). Zebra mussels and other benthic molluscs were sampled in October, and zebra mussel numbers on Q. quadrula outside exclosures were significantly higher in October than in June. Densities of zebra mussels on Q. quadrula and colonization plates were much higher in small-mesh and large-mesh treatments that excluded large fish than open treatments. Mean (±1 SE) densities of zebra mussels/unionid were also higher inside (1041 ± 103) than outside (6.9 ± 1.5) exclosures in October. These results indicate that large-bodied molluscivores (e.g., common carp, freshwater drum, channel catfish) can limit zebra mussel numbers in coastal wetlands. Densities of other molluscs (Sphaeriidae, Corbiculidae, Gastropoda, and Unionidae) were not different in sediments of exclosures and uncaged areas, suggesting that fish can have a greater impact on numbers of attached zebra mussels than benthic molluscs.
Measuring The Benefits Of Voice-Over-Internet Protocol (VOIP)

The following study will analyze the concept of VoIP in a business environment. It will examine the technical aspects associated with VoIP installations and the organizational structure which best facilitates the process. Furthermore, it will discuss the quantitative and non-quantitative methodologies applicable to the cost and profitability of VoIP in the business environment. Lastly, the paper will focus on recent regulation topics surrounding the new technology and provide examples of current applications.
The Dissipation of Excess Heat from Water Systems

A model for the prediction of excess temperature is shown to have the form of the classical diffusion equation. The excess temperature in this model is defined as the difference between the actual water temperature and the water temperature which would have occurred provided that a particular heat source, such as a power plant, had never existed. This definition of excess temperature is convenient because it directly represents the incremental effect that a heat source has on a water system and, provided that historical water temperature records are available, the excess temperature can be predicted without the use of solar or atmospheric radiation data. A prediction equation for the surface transfer coefficient for excess heat illustrates that this coefficient is primarily dependent upon the water temperature and wind speed, and that it is almost independent of the humidity and temperature of the air.
Apolipoprotein C-II Deficiency with Encephalopathy

Two siblings with severe hyperchylomicronemia and encephalopathy in early infancy are reported from Starship Children’s Hospital, Aukland, New Zealand.
Quantitative Optical Coherence Tomography Angiography Features and Visual Function in Eyes With Branch Retinal Vein Occlusion.

Purpose To measure the vascular density and foveal avascular zone (FAZ) area in the deep and superficial retinal vascular networks using optical coherence tomography angiography (OCTA) in patients with branch retinal vein occlusion (BRVO). Design Retrospective observational case series. Methods Patients with unilateral BRVO involving the macula were enrolled. OCTA was performed on the BRVO and fellow eyes. Macular vascular density, FAZ area, and foveal thickness were measured in all eyes. Results Seventeen eyes of 17 patients met inclusion criteria. The mean overall vascular density measured in the entire scan was lower in BRVO eyes compared to fellow eyes in both the superficial (48.07% vs 52.60%, respectively; P P P P = .04). A negative correlation was found between the logarithm of the minimal angle of resolution (logMAR) visual acuity and the overall density in superficial (r = −0.40, P = .02) and deep (r = −0.38, P = .03) networks. The mean FAZ area in BRVO eyes was significantly lower only at the level of the deep network when compared to the fellow eyes (0.519 mm 2 vs 0.410 mm 2 , respectively; P = .02) and correlated positively with logMAR (r = 0.34, P = .04). Conclusion In eyes with BRVO, quantitative OCTA measurements confirm decreased vascular density in both the superficial and deep vascular networks. Moreover, vascular density and FAZ area appear to correlate with visual function.
Morphology in Malay–English biliteracy acquisition: an intervention study

This intervention study examined the effect of English morphological instruction on the development of English as well as Malay morphological awareness and word reading abilities among Malay–English bilingual fourth graders in Singapore, where English is the medium of instruction. The intervention group experienced semester-long instruction in English derivation; the control group was taught with their regular English curriculum. Both groups were tested with derivational awareness and derived word decoding tasks in English and Malay at the end of Grade 3 prior to the intervention (pre-test) and at the end of the first semester of Grade 4 right after the intervention (post-test). There was no significant difference between the two groups on all tasks at pre-testing. Significant intervention effects were found on the development of English abilities in that the intervention group's performance gain was significantly greater than that of the control group on all English tasks except the derived decoding flue...
Experimental Study on the Infection of Freshwater Snails with Angiostrongylus cantonesis

Objective To study the infectivity of Angioslrongylus canlonensis on the freshwater snails,Achatina fulica,Bellamya aeruginosa,and Cipangopaludina chinensis.Method Snails were infected by the first-stage larvae of A.canlonensis under the same conditions.Groups of twenty snails of each species were randomly sampled after exposure to the larvae for 2、4、8、12,24 hours.Each group of snails was kept separately in tanks equipped with water filter,and the water temperature was maintained at(24±1)℃.In the first two weeks,the number of viable snails was recorded.The weight of the snails and the worm burden of each snail was monitored starting from 2 weeks after infection.Result The death rate of snails reached a maximum at day-5 after infection,and the mortality was similar in all 3 different species of snails.Both the death rate and infection rate were not correlated with the exposure time and snail species.At 8 to 24 hours after infection,the worm burden in B.aeruginosa is significantly increased(P 0.05).For the A.Fulica,the worm burden is significantly increased at 24 hours after infection(P 0.05).For the C.chinensis,the worm burden was similar at all time point(2～24 hours) after infection(P 0.05).Both the worm burden and worm density in A.fulica were significantly higher than B.aeruginosa,and C.chinensis at 8～24 hours after infection.Conclusion Both A.fulica and B.aeruginosa are susceptible to the infection by A.cantonensis.The susceptibility of A.fulica is higher than the other species.
Practical statistical static timing analysis with current source models

This paper considers the practical nuances of using current source gate models in an industrial statistical timing analysis environment. Specifically, the memory overhead of a naive implementation combining statistical and current source models to obtain and store gate output waveforms is found to be impractical for large microprocessor designs. A study is performed to observe variational gate output waveforms, and a technique is presented to store the waveforms in a memory efficient manner with minimal accuracy impact. The presented technique is validated over a set of 14 nanometer designs, and has enabled the usage of current source models in our industrial statistical timing analysis flow. Results demonstrate slack accuracy improvements of up to 17 picoseconds with a 1.15X run-time overhead and 1.1 gigabytes per million-gates memory overhead in comparison to an existing flow.
Two Charter School Principals’ Engagement in Instructional Leadership:

This comparative case (Merriam, 2009) study explored two charter school principals’ engagement in instructional leadership. Analysis of three data sources—interviews, observations, and documents—re...
Observation of Brønsted acid sites of DY zeolite with deuterium NMR

Abstract Solid-state deuterium NMR has been used to detect Bronsted acid sites and non-acidic silanols in D-exchanged zeolites. The quadrupolar coupling constant for Bronsted sites in DY zeolite is 234±2 kHz, and the sites are axially symmetric. This reduction by 1 4 from the water OD coupling constant is indicative of the acidic character of the OD bond. The acid deuterons are immobile at room temperature on a millisecond timescale. Effects of reversible adsorption of ammonia are readily monitored through changes in peaks corresponding to OD and O − NH 3 D + species.
Impact of a Clinical Solid Organ Transplant Pharmacist on Tacrolimus Nephrotoxicity, Therapeutic Drug Monitoring, and Institutional Revenue Generation in Adult Kidney Transplant Recipients.

Context:Tacrolimus requires close therapeutic drug monitoring (TDM) to ensure efficacy and minimize adverse effects. Pharmacists are uniquely positioned on transplant teams to interpret levels and ...
No evidence of recent (1995-2013) decrease of yellow-cedar in Alaska

Climate change is expected to impact forests worldwide, and yellow-cedar (Callitropsis nootkatensis (D. Don) Oerst. ex D.P. Little) decline has been used as an example of how changing climate can impact a tree species. However, most previous research has not placed yellow-cedar decline within the context of yellow-cedar overall. We used a 2004–2013 regional inventory of the temperate rainforest of Alaska (671 plots with yellow-cedar) to estimate current attributes and a subset of 564 remeasured plots (established 1995–1998) to estimate recent change. Results show that in unmanaged forests, yellow-cedar live tree basal area recently (1995–1998 to 2004–2013) increased, with a 95% confidence interval of a 0.3% to 3.3% increase per decade. Yellow-cedar has a relatively low mortality rate, 0.41% of trees per year. An analysis of live tree to snag ratios was consistent with elevated mortality of yellow-cedar prior to 1995 but also indicated that little range contraction had occurred. The large numbers and wide ...
A high speed SOI technology with 12 ps/18 ps gate delay operating at 5 V/1.5 V

A high speed Silicon-on-Insulator technology was developed, and a high performance circuit operating at very low power supply voltages was realized. The SOI MOSFETs fabricated on ultra-thin SOI film are fully-depleted and demonstrate excellent short channel behavior. At power supply voltage of V/sub DD/=1.5 V and room temperature, typical propagation delay of 18 ps/stage was obtained for depletion-mode NMOS inverter ring oscillator. The best result shows delay time of 14 ps/stage at V/sub DD/=1.5 V for ring oscillator fabricated on 500 AA SOI film with T/sub ox/=70 AA. This are the best results reported for power supply voltage of 1.5 V at room temperature. >
War at the Door: Evolutionary Considerations of Warfare and Female Fighters

Warfare studies in anthropology and archaeology are often predicated on the specific identification of battlefields and warriors. But the lived experience of violence in times of war transcends normative social and spatial boundaries. In this chapter, a Late Prehistoric Oneota/Mississippian site in the Central Illinois River Valley serves as a case study for questioning the binary structures at the core of many traditional warfare studies, such as differentiation between combatant versus noncombatant, warrior versus civilian, and even between battlefields and other spaces within a broader landscape of violence. Though heuristically useful, deconstruction of these categories opens new realms of analysis where we feel that women’s significant and active participation in warfare has particular potential to be elucidated. Although much evolutionary research regarding warfare and violence has been historically focused on males’ physical and mental propensity for aggression and warriorhood, we focus instead on the evolutionary biology and psychology of motherhood as a motivator for situational female aggression.
Nature and function of rules

Surveyed Year 1 and 2 teachers in Australia about their classroom rules. Found that teachers have about six rules for their classes relating to pupil-pupil relations, completing academic tasks, movement around the classroom, property, safety, and other. Most rules concerned pupil-pupil interactions, and all rules can be seen as a way of socializing new students into the school environment.
Large-scale interaction effects reveal missing heritability in schizophrenia, bipolar disorder and posttraumatic stress disorder

Genetic susceptibility factors behind psychiatric disorders typically contribute small effects individually. A possible explanation for the missing heritability is that the effects of common variants are not only polygenic but also non-additive, appearing only when interactions within large groups are taken into account. Here, we tested this hypothesis for schizophrenia (SZ) and bipolar disorder (BP) disease risks, and identified genetic factors shared with posttraumatic stress disorder (PTSD). When considered independently, few single-nucleotide polymorphisms (SNPs) reached genome-wide significance. In contrast, when SNPs were selected in groups (containing up to thousands each) and the collective effects of all interactions were estimated, the association strength for SZ/BP rose dramatically with a combined sample size of 7187 cases and 8309 controls. We identified a large number of genes and pathways whose association was significant only when interaction effects were included. The gene with highest association was CSMD1, which encodes a negative regulator of complement activation. Pathways for glycosaminoglycan (GAG) synthesis exhibited strong association in multiple contexts. Taken together, highly associated pathways suggested a pathogenesis mechanism where maternal immune activation causes disruption of neurogenesis (compounded by impaired cell cycle, DNA repair and neuronal migration) and deficits in cortical interneurons, leading to symptoms triggered by synaptic pruning. Increased risks arise from GAG deficiencies causing complement activation and excessive microglial action. Analysis of PTSD data sets suggested an etiology common to SZ/BP: interneuron deficiency can also lead to impaired control of fear responses triggered by trauma. We additionally found PTSD risk factors affecting synaptic plasticity and fatty acid signaling, consistent with the fear extinction model. Our results suggest that much of the missing heritability of psychiatric disorders resides in non-additive interaction effects.
Targeted Radionuclide Therapy: An Evolution Toward Precision Cancer Treatment

OBJECTIVE. This article reviews recent developments in targeted radionuclide therapy (TRT) approaches directed to malignant liver lesions, bone metastases, neuroendocrine tumors, and castrate-resistant metastatic prostate cancer and discusses challenges and opportunities in this field. CONCLUSION. TRT has been employed since the first radioiodine thyroid treatment almost 75 years ago. Progress in the understanding of the complex underlying biology of cancer and advances in radiochemistry science, multimodal imaging techniques including the concept of “see and treat” within the framework of theranostics, and universal traction with the notion of precision medicine have all contributed to a resurgence of TRT.
Gene co-expression networks identify Trem2 and Tyrobp as major hubs in human APOE expressing mice following traumatic brain injury.

Traumatic brain injury (TBI) is strongly linked to an increased risk of developing dementia, including chronic traumatic encephalopathy and possibly Alzheimer's disease (AD). APOEe4 allele of human Apolipoprotein E (APOE) gene is the major genetic risk factor for late onset AD and has been associated with chronic traumatic encephalopathy and unfavorable outcome following TBI. To determine if there is an APOE isoform-specific response to TBI we performed controlled cortical impact on 3-month-old mice expressing human APOE3 or APOE4 isoforms. Following injury, we used several behavior paradigms to test for anxiety and learning and found that APOE3 and APOE4 targeted replacement mice demonstrate cognitive impairments following moderate TBI. Transcriptional profiling 14days following injury revealed a significant effect of TBI, which was similar in both genotypes. Significantly upregulated by injury in both genotypes were mRNA expression and protein level of ABCA1 transporter and APOJ, but not APOE. To identify gene-networks correlated to injury and APOE isoform, we performed Weighted Gene Co-expression Network Analysis. We determined that the network mostly correlated to TBI in animals expressing both isoforms is immune response with major hub genes including Trem2, Tyrobp, Clec7a and Cd68. We also found a significant increase of TREM2, IBA-1 and GFAP protein levels in the brains of injured mice. We identified a network representing myelination that correlated significantly with APOE isoform in both injury groups. This network was significantly enriched in oligodendrocyte signature genes, such as Mbp and Plp1. Our results demonstrate unique and distinct gene networks at this acute time point for injury and APOE isoform, as well as a network driven by APOE isoform across TBI groups.
Quantitative and Mechanistic Understanding of AZD1775 Penetration across Human Blood-Brain Barrier in Glioblastoma Patients Using an IVIVE-PBPK Modeling Approach.

Purpose: AZD1775, a first-in-class, small-molecule inhibitor of the Wee1 tyrosine kinase, is under evaluation as a potential chemo- and radiosensitizer for treating glioblastoma. This study was to prospectively, quantitatively, and mechanistically investigate the penetration of AZD1775 across the human blood–brain barrier (BBB). Experimental Design: AZD1775 plasma and tumor pharmacokinetics were evaluated in 20 patients with glioblastoma. The drug metabolism, transcellular passive permeability, and interactions with efflux and uptake transporters were determined using human derived in vitro systems. A whole-body physiologically based pharmacokinetic (PBPK) model integrated with a four-compartment permeability-limited brain model was developed for predicting the kinetics of AZD1775 BBB penetration and assessing the factors modulating this process. Results: AZD1775 exhibited good tumor penetration in patients with glioblastoma, with the unbound tumor-to-plasma concentration ratio ranging from 1.3 to 24.4 (median, 3.2). It was a substrate for ABCB1, ABCG2, and OATP1A2, but not for OATP2B1 or OAT3. AZD1775 transcellular passive permeability and active efflux clearance across MDCKII–ABCB1 or MDCKII–ABCG2 cell monolayers were dependent on the basolateral pH. The PBPK model well predicted observed drug plasma and tumor concentrations in patients. The extent and rate of drug BBB penetration were influenced by BBB integrity, efflux and uptake active transporter activity, and drug binding to brain tissue. Conclusions: In the relatively acidic tumor microenvironment where ABCB1/ABCG2 transporter-mediated efflux clearance is reduced, OATP1A2-mediated active uptake becomes dominant, driving AZD1775 penetration into brain tumor. Variations in the brain tumor regional pH, transporter expression/activity, and BBB integrity collectively contribute to the heterogeneity of AZD1775 penetration into brain tumors. Clin Cancer Res; 23(24); 7454–66. ©2017 AACR. See related commentary by Peer et al., p. 7437
Targeting T cell senescence in the tumor microenvironment for tumor immunotherapy

Understanding the molecular mechanisms involved in creating and sustaining the tumor suppressive microenvironment is critical for the development of novel anti-tumor therapeutic strategies. Regulatory T cells (Treg) are a key player for the tumor immunosuppressive microenvironment. However, the molecular processes and functions of suppressed responder T cells mediated by Treg cells remain largely unknown. We discovered a novel suppressive mechanism whereby human Treg cells induce senescence in naive and effector T cells that then exhibit potent suppressive activity and amplify immune suppression. Treg-induced senescent T cells were distinctly different from the exhausted or anergic T cells based on the transcriptome analyses and phenotypic profiles. We further identified that the nuclear kinase ataxia-telangiectasia mutated protein (ATM)-induced DNA damage was critical and the main cause for the induction of responder T cell senescence and dysfunction mediated by human Treg cells. In addition, MAPK ERK1/2 and p38 were involved in the regulation of senescence process in responder T cells. Importantly, we further revealed that human Treg-induced senescence and suppressor function could be blocked by specific ATM signaling and/or ERK1/2 and p38 signaling inhibition in vitro and in vivo in animal models. Our studies identify a novel molecular mechanism responsible for human Treg cell suppression, and provide new insights relevant for the development of strategies capable of preventing and/or reversing Treg-induced immune suppression for tumor immunotherapy. Funding Support: Supported by the grants from the Melanoma Research Alliance, American Cancer Society and the National Institutes of Health.
The kidney in health and disease XXIII. The pathophysiology of uremia.

The incidence of full-blown uremic syndrome is decreasing because most patients in renal failure are started on dialysis before the uremia becomes symptomatic. Research in the pathophysiology of ur...
Trends in Health Insurance and Type Among Military Veterans: United States, 2000-2016.

Objectives. To describe long-term national trends in health insurance coverage among US veterans from 2000 to 2016 in the context of recent health care reform.Methods. We used 2000 to 2016 National Health Interview Survey data on veterans aged 18 to 64 years to examine trends in insurance coverage and uninsurance by year, income, and state Medicaid expansion status. We also explored the current proportions of veterans with each type of insurance by age group.Results. The percentage of veterans with private insurance decreased from 70.8% in 2000 to 56.9% in 2011, whereas between 2000 and 2016 Department of Veterans Affairs (VA) health care coverage (only) almost tripled, Medicaid (without concurrent TRICARE or private coverage) doubled, and TRICARE coverage of any type tripled. After 2011, the percentage of veterans who were uninsured decreased. In 2016, low-income veterans in Medicaid expansion states had double the Medicaid coverage (41.1%) of low-income veterans in nonexpansion states (20.1%).Conclusion...
Lhx2 regulates temporal changes in chromatin accessibility and transcription factor binding in retinal progenitor cells

Retinal progenitor cells (RPCs) pass through multiple stages of developmental competence, where they successively acquire and lose the ability to generate individual cell subtypes. To identify the transcriptional regulatory networks that control these transitions, we conducted epigenomic and transcriptomic profiling of early and late-stage RPCs and observed a developmentally dynamic landscape of chromatin accessibility. Open chromatin regions that showed stage-specificity, as well as those shared by early and late-stage RPCs, were selectively targeted by the homeodomain factor Lhx2, which is expressed throughout retinal neurogenesis but also regulates many stage-specific processes in RPCs. Stage-specific Lhx2 binding sites were frequently associated with target sites for transcription factors that are preferentially expressed in either early or late-stage RPCs, and which were predicted to possess pioneer activity. Lhx2 loss of function in RPCs led to a loss of chromatin accessibility at both direct Lhx2 target sites and more broadly across the genome, as well as a loss of binding by transcription factors associated with stage-specific Lhx2 target sites. These findings demonstrate a central role for Lhx2 in control of chromatin accessibility in RPCs, and identify transcription factors that may guide stage-specific target site selection by Lhx2.
Proton radiography for relativistic proton beam therapy

Proton beam radiation therapy is at the forefront of modern techniques for cancer treatment, due to its high level of radiation-dose deposition accuracy. This treatment accuracy, however, is limited by the ability to position the treatment beam within the patient's anatomy. Typically, the patient's position is registered orthogonally, using X-ray imaging. However, if instead, beam's-eye-view imaging were enabled by proton radiography, dose deposition measurements could be improved with intrinsically-registered patient positioning. At a typical treatment facility, with a maximum proton energy on the order of 250 MeV, imaging capabilities are limited by the high degree of multiple-Coulomb scatter protons accumulate before exiting the patient. However, in increasing the proton energy from 250 MeV to 800 MeV, the accumulated scatter is reduced by a factor of five, and, coupled with a magnetic-lens, collimated imaging system, enables high-resolution, high-contrast imaging. Further, based on results from Geant4, the dose profile of this higher energy beam is tightly constrained, a fact which may be exploited in the future to further increase treatment accuracy. The full-width half-max of the dose-deposition kernels at 33.4 cm depth (the 250-MeV Bragg peak) are 1.56 cm for 250-MeV protons, compared with 0.52 cm for 800-MeV protons. At 1-cm downstream of this point, the 250-MeV kernel has dropped off to 32%, while the 800-MeV dose is still at 95%. An 800-MeV proton treatment plan exploiting the constrained lateral profile would utilize techniques developed for photon therapy, to deliver the dose from 360° and tightly constrain the dose, stereotactically.
The Uplift-Climate Connection: A Synthesis

Viewed in their entirety, the chapters in this volume confirm earlier hypotheses1–5 that tectonic uplift has played a prominent role in climatic change during the Cenozoic. This chapter synthesizes evidence published in this volume, supplemented by other publications in recent years, to update the status of the uplift-climate hypotheses. It also incorporates criticisms of the hypotheses and integrates relevant information from meterological, climatological, geomorphic, and sedimentological sources.
THERMAL AND CATALTYIC CLEAVAGE OF ARYL-ALKYL COAL LINKAGES

Publisher Summary This chapter discusses thermal and catalytic cleavage of aryl–alkyl coal linkages. The chapter illustrates the measured rates of ipso-displacement of benzyl groups from arenes containing one to four aromatic rings in a 1:1 mixture of anthracene and 9,10-dihydroanthracene at 400°C. The chapter presents experiments that were performed in sealed fused-silica ampoules containing 10 wt% substrate in a 1:1 anthracene/dihydroanthracene mixture, and were analyzed by gas chromatography/mass spectrography (GC/MS). The measured rates were expressed as defined first-order rate constants. Displacement was observed in all cases, with the reaction becoming progressively more facile as the ΔH0 for H-atom addition to the aromatics became more negative. The experimental evidence demonstrated that cleavage induced by H-transfer is general for benzyl and alkyl linkages to aromatic ring systems.
The boundaries of instance-based learning theory for explaining decisions from experience

Most demonstrations of how people make decisions in risky situations rely on decisions from description, where outcomes and their probabilities are explicitly stated. But recently, more attention has been given to decisions from experience where people discover these outcomes and probabilities through exploration. More importantly, risky behavior depends on how decisions are made (from description or experience), and although prospect theory explains decisions from description, a comprehensive model of decisions from experience is yet to be found. Instance-based learning theory (IBLT) explains how decisions are made from experience through interactions with dynamic environments (Gonzalez et al., 2003). The theory has shown robust explanations of behavior across multiple tasks and contexts, but it is becoming unclear what the theory is able to explain and what it does not. The goal of this chapter is to start addressing this problem. I will introduce IBLT and a recent cognitive model based on this theory: the IBL model of repeated binary choice; then I will discuss the phenomena that the IBL model explains and those that the model does not. The argument is for the theory's robustness but also for clarity in terms of concrete effects that the theory can or cannot account for.
Microeconomic Effects of Women Entering the Labor Force

In the United States, increasing numbers of women, especially those with children, now are choosing to contribute financially to their families by earning money in paid employment.1 The basis for this decision is that they can take employment hours and contribute more from net cash earnings than by staying at home and producing additional products and services with those hours. Their income helps with family bills and enhances the family level of living. It also adds to the real national income by increasing the total quantity of goods and services produced in our economy. In the 1970s, real per capita income after taxes rose more than 25%.2 As the size of the average family declines, even constant income would mean more per capita. If women had not moved into the labor force, our national level of living might have fallen sharply, instead of increasing.
Identifying and Advancing Best Practices for the Labeling and Dosing of Pediatric Liquid Medications: Progress and Challenges.

What's New The NIH-funded SAFE Rx for Kids study has identified best practices for the labeling/dosing of pediatric liquid medications. Findings support use of pictographic instructions and optimized provision of dosing tools, along with careful selection of the unit of measurement used.
Perioperative antibiotics should be used for placement of implanted central venous ports: A propensity analysis evaluating risk.

Abstract Objective To quantify risk for CRI based on PABX use in CVAP placement for cancer patients. Summary background data : Central venous access ports (CVAP) are totally implanted devices used for chemotherapy. There is a temporal risk for catheter related infection (CRI) to insertion and perioperative prophylactic antibiotics (PABX) use is a contested issue among practitioners. Methods Data was collected from a single center, academic oncology center. Treatment with a perioperative PABX was compared to non-treatment, to examine the incidence of 14-day CRI. Propensity scores with matched weights controlled for confounding, using 15 demographic, procedural and clinical variables. Results From 2007 to 2012, 1,091 CVAP were placed, where 59.7 % received PABX. The 14-day CRI rate was 0.82%, with 78% of those not receiving PABX. While results did not achieve statistical significance, use of PABX was associated with a 58% reduction in the odds of a 14-day CRI (OR = 0.42, 95% CI: 0.08-2.24, p = 0.31). Conclusion The findings suggest a reduction in early CRI with the use of PABX. Since CRI treatment can range from a course of oral antibiotics, port removal, to hospital admission, we suggest clinicians consider these data when considering PABX in this high-risk population.
Possession as the Root of Title

Law then is not philosophy, and the treatment of its fundamental premises may lack the quest for universals that is the hallmark of much philosophical inquiry. Pierson v. Post* perhaps the leading case on the subject, is illustrative of the legal reluctance to examine first principles afresh. The case arose out of the following facts: The plaintiff below, Post, was pursuing a fox across an unowned stretch of beach with his hounds when Pierson, almost from nowhere, rode up to capture the fox, which he kept even after Post demanded it be handed over. Post then sued Pierson claiming that Pierson had "indirectly" injured Post by taking the fox into his possession. For the purposes of the argument, it was assumed, but not demonstrated, that the fox was unowned before the incident took place. The question was whether Post could get back "his" fox (or its value) from Pierson.
PERCUTANEOUS TRANSVALVULAR MICROAXIAL VENTRICULAR ASSIST DEVICE TO DECOMPRESS THE LEFT VENTRICLE IN PATIENTS UNDERGOING VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION FOR CARDIOGENIC SHOCK: A SYSTEMATIC REVIEW AND METANALYSIS

Veno-Arterial Extracorporeal membrane oxygenator (VA ECMO) is widely used for supportive care during severe cardiogenic shock. While immediate improvement in mean arterial pressure is seen, upstream flow from VA ECMO leads to an increase in the afterload of an already failing left ventricle (LV).
Lower Socioeconomic Status Associated with Decreased Completion of Exercise Rehabilitation in Patients with Pulmonary Hypertension

Purpose Patients with pulmonary hypertension (PH) who concurrently have low socioeconomic status (SES) present with more advanced illness and have increased risk of death. Exercise rehabilitation is an underutilized therapy that improves exercise capacity and quality of life. Whether disparities in rehabilitation completion exist is unknown. Methods We performed a cross-sectional survey of patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH) who attended the PH Association (PHA) Research Room during the biennial conference. Participants completed a survey of demographic and clinical characteristics that inquired about prior referral and completion of rehabilitation and the MacArthur Scale of Subjective Social Status (MSSS). The MSSS is a validated survey of SES that asks participants to rate where they are on a ladder ranging from 1-10 in regards to income, occupation, or education compared to other people in the US. The primary outcome was completion of rehabilitation defined as attendance at >75% of sessions. The primary predictor was SES as measured by the MSSS grouped in tertiles. Multivariable logistic regressions performed to examine association between SES and rehabilitation completion adjusted for age and WHO functional class. Using the final model, the predicted probability of completion by SES tertile was estimated. Results We enrolled 62 participants with a mean age of 51.5 (± SD; 15.1) years, of whom 87% (n =52) were female. 48.4% (n = 30) had never been referred, 4.8% (n = 3) were referred and didn't complete, and 51.6% (n = 32) had completed rehabilitation. In the multivariable analysis, participants in the lowest SES tertile had greater than 80% lower odds of being referred and completing rehabilitation than participants in the highest SES tertile (OR 0.17, 95% CI 0.04 - 0.78; p value = 0.22). Using the final model, only 25.5% (95% CI, 9.3 - 41.6) of participants in the lowest SES tertile were predicted to complete rehabilitation compared to 63.0% (38.4 - 87.6) in the highest SES tertile. Conclusion Lower SES participants with PAH and CTEPH were less likely to complete exercise rehabilitation. Decreased access to effective therapies could account for some of the excess risk seen by lower SES patients with PAH. Policies to enable equity of access to exercise rehabilitation should be explored.
4-(Lithiomethyl)-2,6-di-tert-butylpyridine: A Useful Precursor for the Synthesis of Bis(2,6-di-tert-butyl)pyridyl Compounds.

The known lithiomethylpyridine (I) mentioned in the title is dimerized upon treatment with iodine, yielding the ethylene-bridged bipyridine (II).