cssi/SciSciGPT-SciSciNet huggingface dataset:
Impairment of Thiamine Transport at the GUT-BBB-AXIS Contributes to Wernicke’s Encephalopathy

Wernicke's encephalopathy, a common neurological disease, is caused by thiamine (vitamin B1) deficiency. Neuropathy resulting from thiamine deficiency is a hallmark of Wernicke-Korsakoff syndrome in chronic alcohol users. The underlying mechanisms of this deficiency and progression of neuropathy remain to be understood. To uncover the unknown mechanisms of thiamine deficiency in alcohol abuse, we used chronic alcohol consumption or thiamine deficiency diet ingestion in animal models. Observations from animal models were validated in primary human neuronal culture for neurodegenerative process. We employed radio-labeled bio-distribution of thiamine, qualitative and quantitative analyses of the various biomarkers and neurodegenerative process. In the present studies, we established that disruption of thiamine transport across the intestinal gut blood-brain barrier axis as the cause of thiamine deficiency in the brain for neurodegeneration. We found that reduction in thiamine transport across these interfaces was the cause of reduction in the synthesis of thiamine pyrophosphate (TPP), an active cofactor for pyruvate dehydrogenase E1α (PDHE1α). Our findings revealed that decrease in the levels of PDHE1α cofactors switched on the activation of PD kinase (PDK) in the brain, thereby triggering the neuronal phosphorylation of PDHE1α (p-PDHE1α). Dysfunctional phosphorylated PDHE1α causes the reduction of mitochondrial aerobic respiration that led to neurodegeneration. We concluded that impairment of thiamine transport across the gut-BBB-axis that led to insufficient TPP synthesis was critical to Wernicke-neuropathy, which could be effectively prevented by stabilizing the thiamine transporters.
miRcomp-Shiny : Interactive assessment of qPCR-based microRNA quantification and quality control algorithms

The miRcomp-Shiny web application allows interactive performance assessments and comparisons of qPCR-based microRNA expression and quality estimation methods using a benchmark data set. This work is motivated by two distinct use cases: (1) selection of methodology and quality thresholds for use analyzing one's own data, and (2) comparison of novel expression estimation algorithms with currently-available methodology. The miRcomp-Shiny application is implemented in the R/Shiny language and can be installed on any operating system on which R can be installed. It is made freely available as part of the miRcomp package (version 1.3.3 and later) available through the Bioconductor project at: http://bioconductor.org/packages/miRcomp. The web application is hosted at https://laurenkemperman.shinyapps.io/mircomp/. A detailed description of how to use the web application is available at: http://lkemperm.github.io/miRcomp_shiny_app
Moral Injury and Human Relationship: A Conversation

This article brings together years of personal reflection on my own experience of war as an army veteran. I argue that moral injury is about human relationship, and therefore I write in a conversational tone with the Reader. I explore two oft-cited definitions of moral injury (Shay and Litz et al.) and Dietrich Bonhoeffer’s use of the term “conscience” by critically reflecting on my own experience, and I invite readers to do the same.
Emily Dickinson “in the Other’s Eyes – ”

One remarkable aspect of Emily Dickinson’s writing is the startling way that it neatly fits other poets and thinkers into its own poetic frameworks. With a devastating combination of modesty and br...
Electrophysiological Assessment of Dopamine Receptor Subtypes

Scientific approaches to the characterization of brain systems can be globally classified into those approaches which demonstrate the presence of a phenomenon, and those which attribute a function to the described phenomenon. These approaches are interdependent and both are essential for understanding the whole organism. Previous chapters in this volume provide reviews of the presence and distribution of subtypes of central dopamine (DA) binding sites. Behavioral function has now been correlated with each of these proposed receptor groups. The present review is concerned with electrophysiological consequences of DA receptor activation. Electrophysiology provides assessment of function at the single cell level and allows for discrimination among neuronal systems. Therefore, electrophysiology serves as a bridge between the identification and anatomical location of a receptor, and the characterization of whole animal behaviors resulting from receptor activation.
Tumor-derived G-CSF promotes granulocytic MDSC development in vivo (66.34)

Myeloid-derived suppressor cells (MDSC) comprise a heterogeneous population of myeloid cells with the capacity to suppress tumor immunity. Consequently, these cells represent a significant impediment to effective cancer immunotherapy. While the mechanisms by which these cells mediate immunosuppression is well-established, details on how they develop remain poorly understood. Broadly speaking, it is known that tumor-derived factors play significant roles in diverse aspects of MDSC biology. Given that MDSC accumulation is a result of altered myelopoiesis and that a major subset is granulocytic, we tested the hypothesis that tumor-derived granulocyte-colony stimulating factor (G-CSF) promotes MDSC development. Using both implantable and autochthonous mouse mammary tumor models, we observed abundant amounts of G-CSF in vivo, which correlated with a massive accumulation of granulocytic MDSC. To determine a causal role of G-CSF in MDSC generation, we established both gain- and loss-of-function approaches. First, administration of recombinant G-CSF alone elicited immunosuppressive granulocytic MDSC. Secondly, over-expression of G-CSF in G-CSF-negative tumors led to granulocytic MDSC accumulation. Lastly, inhibiting G-CSF culminated in a significant reduction of granulocytic MDSC. Collectively, our studies demonstrate the importance of tumor-derived G-CSF in MDSC development, thus providing new insights into the identity of putative targets for therapeutic applications.
A model of pain behaviors in freely moving rats generated by controllable electrical stimulation of the peripheral nerve

Abstract Background Neuropathic pain patients have described experiencing unprovoked, intermittent pain attacks with shooting, stabbing, and burning qualities. Rodent models used in previous literature usually only involve acute exposure, and/or are unable to manipulate the stimulation intensity in vivo by the experimenter during an experiment. New method This paper describes a method to induce controllable pain behaviors in rodents using a wireless portable electronic device that can be manipulated within the course of an experiment. A stimulating electrode was implanted at the L5 spinal nerve location in Sprague-Dawley rats and our custom-built wireless stimulating device was attached to deliver variable stimulation in freely moving animals (50 Hz, 0.5 V; 100 Hz, 1 V). Results Implantation itself did not induce hypersensitivity as measured by the mechanical paw withdrawal threshold test. Observation of pain behaviors (paw elevation and licking) indicated that high stimulation intensity yielded a significant increase in pain behaviors. Even further, high intensity stimulation resulted in a behavioral “wind-up” of pain behaviors that persisted into the resting period when no stimulation was applied. Comparison with existing methods and conclusions This method can be used to study pain behaviors in a controllable way in freely moving rodents in comparison to existing models that are acute and/or are unable to manipulate the stimulation intensity in vivo.
Disease progression in Myotonic Dystrophy Type 1 during a non-interventional multicenter study (S22.004)

Objective: To determine the responsiveness of clinical outcome assessments to disease progression over 1-year in patients with myotonic dystrophy type 1 (DM1). Background: As targeted treatments for DM1 advance to clinical trials, there is a pressing need for natural history data to assess disease progression and clinical endpoints in a multicenter context. Design/Methods: We conducted a prospective 12-month study of ambulatory adult patients with non-congenital DM1 at 6 sites. Outcome measures included quantitative muscle testing (QMT, 7 bilateral muscles normalized to percent predicted for gender, age, and height), manual muscle testing (MMT, 15 muscles), timed-function tests, forced vital capacity (FVC) and video handgrip opening time. Results: Out of 113 patients enrolled, 95 completed 1-year follow-up (84% retention, 59% women; median age 43 years; range 19–67 years). Composite total, upper- and lower-extremity (LE) QMT strength scores decreased at 1 year by median 6.4% (p=.014), 4.7% (p=.002) and 3.5% of baseline values. Overall, men showed a greater strength decline in most muscle groups than women including handgrip (−9% vs −2%; p Conclusions: There was a measurable decrease in motor function that was most pronounced for muscles preferentially affected by DM1. Gender may have an impact on disease severity and should be considered in DM1 trial design. There was significant decline of supine but not seated FVC, consistent with known involvement of diaphragm. Study Supported by: NIH NS048843 (Wellstone Center), NIH Intramuscular Research Program, Muscular Dystrophy Association, Myotonic Dystrophy Foundation, Marigold Foundation, Biogen Disclosure: Dr. Mankodi has nothing to disclose. Dr. Statland has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Strongbridge, Acceleron, Regeneron, and Sanofi. Dr. Eichinger has nothing to disclose. Dr. Dekdebrun has nothing to disclose. Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Pfizer, Santhera, Sarepta. Dr. Subramony has nothing to disclose. Dr. Kissel has received research support from Novartis, Biomarin, Cytokinetics, CSL Behring, Avexis, Ionis Pharmaceuticals, Quintiles, Axelacare. Dr. Ashizawa has nothing to disclose. Dr. Thornton has nothing to disclose. Dr. Myotonic Dystrophy Research Ne has nothing to disclose.
Perceived social status and mental health among young adolescents: Evidence from census data to cellphones

Adolescents in the United States live amid high levels of concentrated poverty and increasing income inequality. Poverty is robustly linked to adolescents' mental health problems; however, less is known about how perceptions of their social status and exposure to local area income inequality relate to mental health. Participants consisted of a population-representative sample of over 2,100 adolescents (ages 10-16), 395 of whom completed a 14-day ecological momentary assessment (EMA) study. Participants' subjective social status (SSS) was assessed at the start of the EMA, and mental health symptoms were measured both at baseline for the entire sample and daily in the EMA sample. Adolescents' SSS tracked family, school, and neighborhood economic indicators (|r| ranging from .12 to .30), and associations did not differ by age, race, or gender. SSS was independently associated with mental health, with stronger associations among older (ages 14-16) versus younger (ages 10-13) adolescents. Adolescents with lower SSS reported higher psychological distress and inattention problems, as well as more conduct problems, in daily life. Those living in areas with higher income inequality reported significantly lower subjective social status, but this association was explained by family and neighborhood income. Findings illustrate that adolescents' SSS is correlated with both internalizing and externalizing mental health problems, and that by age 14 it becomes a unique predictor of mental health problems. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
The best perinatal depression screening: Is self-administered PHQ2 more feasible than a nurse-administered one?

PURPOSE To assess perinatal depression screening via self-administered PHQ2 (SAP) vs nurse-administered PHQ2 (NAP). DESIGN AND METHODS NAP screening was performed for 3 months, followed by SAP. Data were gathered from visits at 24 to 28 weeks gestation. FINDINGS One hundred twenty-seven patients were in NAP arm, 100 in SAP arm. SAP had higher rates of screening (odds ratio [OR], 3.25; 95% confidence interval [CI], 1.63-6.49), but no difference in positive PHQ2 screens. The SAP rate of therapeutic action for positive screens was lower (OR, 0.24; 95% CI, 0.12-0.50). PRACTICE IMPLICATIONS SAP provided higher perinatal depression screening rates compared to NAP, but decreased therapeutic action.
Dialogue as a Way of Being: Three Fundamental Considerations for Transforming Conflict From Adversarial to Dialogic Relation

The rapidly changing world we live in is fraught with increasing divisions and destructive conflict. Consequently, a resilient social fabric becomes crucial for people to feel included and empowered by their differences. The quality of relationships and the social environments, within which they are constantly being formed, are critical for successfully addressing divisive challenges and the destructive conflicts they might spawn. This chapter proposes a framework of three considerations for transforming conflict: 1. The mode of relationship- how the Self relates to the Other, 2. The perception of conflict, and 3. The social environment and the role of leadership in constructing dialogic environments. Revisiting assumptions pertaining to these considerations can support a shift from the unit of the individual (typically characterizes Western cultural and scientific traditions) to a relational unit. This shift is proposed as a premise for long-term conflict transformation from adversarial interactions into dialogic relation. The latter is suggested as a constructive mode of relationship: a way of being with one another that diminishes a destructive relationship while generating the conditions for benefiting and learning from conflict. The chapter concluded with an example from an educational environment within a relational transformation took place by integrating both micro efforts- consciousness raising to relational forms and dynamics, and macro work of restructuring the social context to advance transformation.
Securing patient satisfaction.

Hospitalists must have and exhibit particular skills and attitudes to ensure that patients and their primary care physicians are satisfied with hospitalist inpatient care. Virtual Mentor is a monthly bioethics journal published by the American Medical Association.
Race, ethnicity, and socioeconomic factors in cholangiocarcinoma: What is driving disparities in receipt of treatment?

BACKGROUND AND OBJECTIVES Race/ethnicity and socioeconomic factors are associated with worse cancer outcomes. Our aim was to determine the association of these factors with receipt of surgery and multimodality therapy for cholangiocarcinoma. METHODS Patients with cholangiocarcincoma in the National Cancer Database were identified. Racial/ethnic groups were defined as non-Hispanic White, non-Hispanic Black, Asian, and Hispanic. Socioeconomic factors were insurance status, income, and education. RESULTS Of 12 095 patients with non-metastatic cholangiocarcinoma, 42% received surgery. Black race was associated with decreased odds of receiving surgery (odds ratio [OR]: 0.66l; P < .001) compared to White patients. Socioeconomic factors accounted for 21% of this disparity. Accounting for socioeconomic and clinicopathologic variables, Black race (OR: 0.73; P < .001), uninsured status (OR: 0.43; P < .001), and Medicaid insurance (OR: 0.63; P < .001) were all associated with decreased receipt of surgery. Of 4808 patients who received surgery, 47% received multimodality therapy. There were no racial/ethnic or socioeconomic differences in receipt of multimodality therapy once patients accessed surgical care. Similar results were seen in patients with advanced disease who received chemotherapy as primary treatment. CONCLUSION Racial/ethnic and socioeconomic disparities exist in treatment for cholangiocarcinoma, however only for primary treatment. In patients who received surgery or chemotherapy, there were no disparities in receipt of multimodality therapy. This emphasizes the need to improve initial access to health care for minority and socioeconomical disadvantaged patients.
Cautions and Possibilities of Online Collective Identity: The It Gets Better Project

Using qualitative content analysis (Schreier M: Qualitative content analysis in practice. Sage Publications, Thousand Oaks, 2012) I examine 318 coming out stories, posted in videos by LGBTQ students and staff at U.S. institutions of higher education, on the It Gets Better Project website. Employing the frame of collective identity in online activism (Polletta F, Jasper JM: Annu Rev Sociol, 27(1):283–305, 2001; Soon C, Kluver R: J Comput-Mediat Commun 19(3):500–515, 2014), I explore how this digital landscape is used to create and support a dominant coming out narrative: declaring, adversity, affirmation, and encouragement. This storyline works to form a collective identity against homophobic discourses while constricting and reinforcing the boundaries of sexuality and gender. Though smaller in number, students also share coming out stories that subvert the prototypical arc, offering different realities of how LGBTQ identity is understood, recognized, and experienced. As the It Gets Better Project has spread globally, this subset of videos provides a cautionary tale of the possibilities of using collective identity in online activism. Namely, when collective identity is used to counter hegemonic power, it both marginalizes the identities of those who do not follow the pre-scripted pattern and contains a superficial promise of progress. However, when examining smaller moments of subversion, collective identity signals a variability that may hold a more constructive message for young viewers.
Topological analysis of X-ray CT data for the recognition and trending of subtle changes in microstructure under material aging

Abstract X-ray computed tomography (CT) is an established non-destructive tool for 3D imaging of multiphasic composites. Numerous applications of X-ray CT in medical diagnosis and materials characterization have been reported, many involving field-specific innovations in the imaging technology itself. Yet, quantitative summarization to link image features to properties of interest has been rare. We address this issue by employing state-of-the-art technics in scalar field topology for the summarization of X-ray CT images of an example biphasic system. By varying processing-parameters we create different microstructures, evolve them through accelerated thermal aging, CT-image them pre- and post-aged, and demonstrate the ability of our image summarization method to systematically track process- and age-related changes, which can often be very subtle. A novel aspect of the algorithm involves recognition over multiple resolution levels, which provides deeper insight into the pattern relationship between grain-like features and their neighbors. The method is general, adaptable to diverse image reconstruction methods and materials systems, and particularly useful in applications where practical constraints on the sample-size limits the reliable use of more complex models, e.g., convolutional neural networks.
Selected Contemporary Gender-Theorists’ Views; or Where Is the Self?

Surprisingly, questions about the concept of Self as framed in the monograph, are not uppermost in this important and vast literature. Nonetheless the views of selected gender-theorists provide intriguing possibilities. The notion of “Concept Amelioration” (Haslanger), for example could prove helpful for the Conceptual Question. And, the “Multiple-Meaning Position” (Bettcher), while aiming to establish the non-marginal status of Trans-women and Trans-men as Women and Men, also allows the positing a new ontological phenotype—Trans-women/Trans-men—an idea elaborated upon in the remaining chapters of the book.
The past, present, and future of brand research

This article discusses the past, present, and future of brand research. We begin by reviewing three historical eras of branding development in the past: the information, attribute, and brand equity eras. Each era is marked by an emphasis on a particular concept of brands and a dominant research methodology during that period. We characterize the present of brand research as the branding era, in which brands have become part of the everyday vocabulary, and the concept of “branding” has been embraced by all types of organizations and people. Finally, we share our perspective on the future of brand research by discussing three major shifts in the brand landscape, mostly influenced by technological advancements such as IoT and their capacity to collect granular data at the individual level. We anticipate that new, exciting opportunities in brand research will continue to open up at the intersection of brands, technologies, and people.
Evaluation of Sampling Methods for Detection of Pathogens from Steel Surfaces; Contact Plates, Foam Swabs, and Flocked Swabs

Background: Contaminated healthcare surfaces can serve as reservoirs for the transmission of pathogens. Sensitive sampling methods are needed to investigate sources of pathogens for implementing effective disinfection strategies and thereby preventing environmental transmission. Conventional approaches employ swabs to sample environmental surfaces. Contact plates represent an alternative approach for sampling healthcare surfaces that does not require lab processing, though little is known about their performance. A contact plate is an agar plate that is overfilled with selective or nonselective media. It can be gently applied to the surface, then simply incubated at a temperature optimal for target organism (s), thus saving time and resources. Methods: In this study, contact plates containing trypticase soy agar with 5% sheep blood (TSAII), foam swabs, and flocked swabs were evaluated for their ability to recover 4 pathogens that persist on healthcare surfaces. Stainless-steel coupons (4 in2) were inoculated with the following pathogens (102 CFU): Acinetobacter baumannii (AB, strain type 12), carbapenemase-producing KPC+ Klebsiella pneumoniae (KP; ATCC BAA-1705); methicillin-resistant Staphylococcus aureus (MRSA; ATCC 43300); and vancomycin-resistant Enterococcus faecalis (VRE; Van A + 256). The plates were allowed to dry 1 hour. Sampling with CPs was performed in 2 ways; (1) a single contact plate was used to sample 1 stainless-steel surface and (2) a composite was collected by 3 sequential contact-plate samplings of the same stainless-steel surface. The contact plates were then incubated at 351C. Foam and flocked swabs were premoistened with phosphate-buffered saline + 0.02% polysorbate 80 (PBST) and were used to sample the stainless-steel coupons. Swabs were held for 1 hour and processed by sonication and vortexing in 5 mL of PBST, then the eluent was cultured and CFU counted. Mean percentage recoveries (%R) relative to the inoculum were calculated and compared. Results: When the %R for all 4 pathogens were pooled, the composite contact-plate sampling method yielded the highest, (P < .05) (66.0%; SD, 0.22), followed by the single contact plate method (39.7%; SD, 0.12), foam swab (32.9%; SD, 0.18), and flocked swab (20.3%; SD, 0.20). The composite contact plate method yielded the highest %R for VRE (102.1 %; SD, 0.17), and the lowest %R was observed when using flocked swabs to recover KP (6.3%; SD, 0.05). Conclusions: The contact-plate composite method may provide investigators with minimal environmental microbiology capacity an alternative method for environmental sampling and detection of organisms from surface areas (4 in 2) with low bioburden. Funding: None Disclosures: None
A Quiet Coup: Balkanizing the U.S. by Eliminating the Electoral College

There are calls for US presidential elections to be changed. The existing Electoral College system, a method that has been in effect in every presidential election since the 1804 approval of the Twelfth Amendment to the US Constitution, is seen by those seeking change as an unjust way for selecting US presidents. Many Democrats remain enraged by the fact that Hillary Clinton received more votes than Donald Trump in 2016 but was not elected president due to the Electoral College’s state-by-state electoral system. A movement is taking place in some state legislatures to adopt a system called the National Popular Vote Interstate Compact [the Compact]. This is a key part of a strategy drafted in 2006 and not yet operative but gaining state signatories. At this point in May 2019 all the current 15 state signatories to the Compact represent states with Democratic-controlled legislatures. The District of Columbia has also voted to join the Compact, bringing the total count to 16. The Investors Business Daily published an analysis of the worst run and best run states from a fiscal perspective. The worst run states included Illinois, California, Massachusetts, New Jersey, Connecticut, Hawaii, New Mexico, New York, and Rhode Island. Each of these states is a signatory to the national popular vote Compact. The best run states included South Dakota, Tennessee, Nebraska, Florida, Utah, Alaska, Oklahoma, Wyoming, New Hampshire, and Montana. With the exception of New Hampshire they are all “Red” states. None is a signatory to the Compact. The National Popular Vote Interstate Compact is an attempt at a “quiet coup” seeking permanent voting control of the office of the US Presidency. As such it offers a perfect recipe for the balkanization of America, contradicting the wisdom of those such as James Madison, one of our Founding Fathers who played a critical role in the formation of our Constitution. Madison recognized the inevitable factionalism of competing interests and diverse cultures in America. The Compact seeks to effectively amend the US Constitution de facto while pretending otherwise. The advocates launched a strategy through the National Popular Vote Interstate Compact knowing they could not gain the required approval of three-fourths of US states to create a national vote simple majority or plurality amendment to the US Constitution in place of the Twelfth Amendment’s Electoral College system.
Maternal Emotion Regulation Difficulties and the Intergenerational Transmission of Risk

Maternal depression is a robust risk factor for heightened internalizing symptoms in offspring. Studies also suggest that maternal depression is associated with greater maternal emotion regulation (ER) difficulties. However, emotion regulation has been conceptualized as a multidimensional construct, and few studies have identified specific components of ER related to maternal depression and the role these components may play in the relationship between maternal depression and child internalizing symptoms. Mothers (n = 73) of young children (ages 4–9; 42 females), recruited from both clinical and community settings, reported their depression symptoms and emotion regulation difficulties. Children’s internalizing symptoms were assessed using both parental report and a semi-structured clinical interview. Regression analyses revealed that maternal depression symptoms were positively related to maternal ER, specifically, limited access to emotion regulation strategies and non-acceptance of emotional responses. Structural equation models revealed that the relation between maternal depression and child internalizing problems was mediated only through mother’s limited access to emotion regulation strategies. Our findings offer new insight for targeting mothers’ limited access to emotion strategies as a novel early intervention method to help break the intergenerational transmission of internalizing symptoms from mother to child.
“The dwarf, the fool, the eunuch are all his”: Venice, Carnival, Reproduction and Plague in Volpone

This essay explores the significance of setting Volpone (1606) in Venice while England was recovering from a major plague epidemic in 1603. The play directly references Venice's long history with t...
Functional analysis and treatment of problem behavior exhibited by children with fragile X syndrome

The efficacy of function-based interventions for the treatment of severe problem behavior exhibited by individuals with intellectual and developmental disabilities (IDD) is well established. However, few studies have reported on behavioral interventions in fragile X syndrome (FXS) specifically. The present study is a consecutive case-series analysis that reports on functional analysis and treatment of problem behavior of nine children with FXS. Assessment findings were consistent with previous research indicating that among individuals with FXS, problem behavior is more commonly maintained by escape from demands and access to tangible items, relative to the broader population of individuals with IDD. Functional analysis-based behavioral interventions resulted in a mean reduction in problem behavior of 95.2% across the nine participants. Additionally, generalization of treatment effects from controlled clinical settings to home, school, and community was demonstrated. The current findings suggest that function-based behavioral interventions shown to be effective with the broader population of individuals with IDD are also effective for individuals with FXS. Our results in combination with those of previous studies describing functional analysis outcomes provide additional evidence for a unique functional behavioral phenotype for severe problem behavior in individuals with FXS. Implications of study findings for early intervention and prevention of problem behavior in children with FXS are discussed.
Gingival and pharyngeal metastasis from a malignant melanoma. Report of a case.

Abstract Malignant melanoma is a rare disease, comprising 1 to 3 per cent of all malignant tumors. Fewer than 2 per cent of all malignant melanomas occur in the oral cavity. Since metastatic malignant melanoma to the gingiva has not been hitherto reported, the case presented here is of interest.
The role of conserved tryptophan and acidic residues in the human dopamine transporter as characterized by site-directed mutagenesis.

The human dopamine (DA) transporter (hDAT) contains multiple tryptophans and acidic residues that are completely or highly conserved among Na(+)/Cl(-)-dependent transporters. We have explored the roles of these residues using non-conservative substitution. Four of 17 mutants (E117Q, W132L, W177L and W184L) lacked plasma membrane immunostaining and were not functional. Both DA uptake and cocaine analog (i.e. 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane, CFT) binding were abolished in W63L and severely damaged in W311L. Four of five aspartate mutations (D68N, D313N, D345N and D436N) shifted the relative selectivity of the hDAT for cocaine analogs and DA by 10-24-fold. In particular, mutation of D345 in the third intracellular loop still allowed considerable [(3)H]DA uptake, but caused undetectable [(3)H]CFT binding. Upon anti-C-terminal-hDAT immunoblotting, D345N appeared as broad bands of 66-97 kDa, but this band could not be photoaffinity labeled with cocaine analog [(125)I]-3beta-(p-chlorophenyl)tropane-2beta-carboxylic acid ([(125)I]RTI-82). Unexpectedly, in this mutant, cocaine-like drugs remained potent inhibitors of [(3)H]DA uptake. CFT solely raised the K(m) of [(3)H]DA uptake in wild-type hDAT, but increased K(m) and decreased V(max) in D345N, suggesting different mechanisms of inhibition. The data taken together indicate that mutation of conserved tryptophans or acidic residues in the hDAT greatly impacts ligand recognition and substrate transport. Additionally, binding of cocaine to the transporter may not be the only way by which cocaine analogs inhibit DA uptake.
Key Issues in Hadronic Physics

A group of fifty physicists met in Duck, NC, Nov. 6-9 to discuss the current status and future goals of hadronic physics. The main purpose of the meeting was to define the field by identifying its key issues, challenges, and opportunities. The conclusions, incorporating considerable input from the community at large, are presented in this white paper.
Locke v. Davey and the Lose-Lose Scenario: What Locke Could have Said, but Didn't

This article was part of a symposium on the funding of religious institutions in light of Locke v. Davey. The article suggests that after Zelman v. Simmons-Harris it seems likely government entities may have to provide funding to religious entities who apply for such funding under a "neutral" funding program. The article also suggests that the Zelman Court's use of the concept of formal neutrality was misguided. The Court in Locke v. Davey missed a golden opportunity to define the boundaries of the Court's new formal neutrality doctrine. The article suggests that the result in Locke was a lose-lose result, because no serious limiting principle on the formal neutrality doctrine was created and a seemingly deserving student was denied a scholarship solely because his chosen profession was the clergy. The article also explores so-called Blaine amendments in light of Locke. The Locke Court held that the state constitutional provision involved in that case was not a Blaine amendment, but these amendments are important because they point to a useful possibility, namely, that states may fund programs that allow funds to flow to religious entities but they need not do so unless the reason for denying such funding involves a purpose to discriminate against religion. The article suggests that while the history of many state Blaine amendments is reprehensible, those amendments later came to serve other purposes and thus may not automatically demonstrate a purpose to discriminate against religion.
Environmental Mutagenesis, Statistics in†

In experiments studying the effects of environmental stimuli on biological organisms, major endpoints of interest include damage to genetic components such as deoxyribonucleic acid (DNA). DNA damage as represented by mutagenic insult(s) is perhaps the most varied of any toxicological endpoint, since the potential mechanisms of genetic damage are so numerous. Statistical issues associated with mutagenicity experiments include construction of models to characterize dose–response and other features of genetic damage, sample size determinations/study design, and the selection of statistical approaches associated with these models and methods; these are briefly discussed Keywords: downturn in dose–response; environmental toxicity; genotoxicology; genetic risk assessment; Salmonella assay; trend testing
Some Evidence on the Declining Effect of Farm Consolidation on Farm Real Estate Prices

Rapid technological change has been a dominating factor in American agriculture in the last quarter of a century. Impact of this factor on the farm real estate market is well documented in agricultural economics literature. As Heady and Fuller and Van Vuuren have noted, technological change has been both land-substituting and land-embodying. This characteristic has resulted in positive pressure on land prices as farmers bid up prices of land for farm enlargement so they can more fully employ their fixed labor and capital resources. As adjustments in farm numbers and sizes have slowed in recent years, the dominating influence of farm consolidation is expected to be moderated. Fuller and Van Vuuren noted this possibility as: â€œâ€¦ given the combination of numbers, ages, and alternatives, intensive efforts to salvage underemployment of operator and family labor by farm enlargement or by substantial employment on other farms have to be approaching an ultimate plateauâ€ . The objective of this paper is to examine impact on farm real estate prices of changing economic conditions in rural areas. Particular attention is given to factors other than farm consolidation. The effect of these structural changes on the land market is empirically tested by reestimating Tweeten and Nelson's model with Georgia data for 1960-1974. (This abstract was borrowed from another version of this item.)
Evaluation of immunization training in the curriculum of first- and third-year pharmacy students

Abstract Objective To assess student pharmacists' perspectives on the curricular timing of the American Pharmacists Association (APhA) Pharmacy-Based Immunization Program and their confidence in providing immunization services. Methods First (P1) and third (P3) professional year students were required to complete the APhA Immunization Certification. An Institutional Review Board-approved, anonymous, voluntary online survey was sent to all participants ( N = 454) to assess the curricular timing and students' confidence in providing immunization services. Results Overall, there were no statistical differences between the P1 and P3 classes in terms of confidence in their knowledge of vaccine-related diseases or in the actual administration. Most P1 students (mean = 4.17) thought it was an appropriate skill to be placed in the P1 year, as did the majority of P3 students (mean = 3.75), although this difference was statistically significant ( P = 0.001). Conclusions Immunization training was well received by all students, with the majority finding it appropriate to complete immunization training in the P1 year. Early placement of immunization training in the curriculum should provide students more opportunities to administer vaccinations during IPPE and places of employment as state law permits.
CIS-ACTING COMPONENTS OF HUMAN PAPILLOMAVIRUS (HPV) DNA REPLICATION : LINKER SUBSTITUTION ANALYSIS OF THE HPV TYPE 11 ORIGIN

Papillomavirus DNA replication requires the viral trans-acting factors E1 and E2 in addition to the host cell's general replication machinery. The origins of DNA replication in bovine and human papillomavirus genomes have been localized to a specific part of the upstream regulatory region (URR) which includes recognition sites for E1 and E2 proteins. To fine map cis-acting elements influencing human papillomavirus type 11 (HPV-11) DNA replication and to determine the relative contributions of such sites, we engineered consecutive linker substitution mutations across a region of 158 bp in the HPV-11 origin and tested mutant origins for replication function in a cell-based transient replication assay. Our results both confirm and extend the findings of others. E2 binding sites are the major cis components of HPV-11 DNA replication, and there is evidence for synergy between these sites. Differential capacity of the three E2 binding sites within the origin to affect replication may be attributed, at least in part, to context. At least one E2 binding site is essential for replication. The imperfect AT-rich palindrome of the E1 helicase binding site is not essential since replication occurs even in the absence of this sequence. However, replication is enhanced by the presence of the palindromic sequence in the HPV-11 origin. Sequence components adjacent to the E1 and E2 binding sites, comprising AT-rich and purine-rich elements and the consensus TATA box sequence, probably contribute to the overall efficiency of replication, though they are nonessential. None of the other cis elements of the HPV-11 origin region analyzed seems to influence replication significantly in the system described. The HPV-11 origin of DNA replication therefore differs from those of the other papovaviruses, simian virus 40 and polyomavirus, inasmuch as an intact helicase binding site and adjacent AT-rich components, while influential, are not absolutely essential.
Citrus aurantium, an Ingredient of Dietary Supplements Marketed for Weight Loss: Current Status of Clinical and Basic Research

Seville orange (Citrus aurantium) extracts are being marketed as a safe alternative to ephedra in herbal weight-loss products, but C. aurantium may also have the potential to cause adverse health effects. C. aurantium contains synephrine (oxedrine), which is structurally similar to epinephrine. Although no adverse events have been associated with ingestion of C. aurantium products thus far, synephrine increases blood pressure in humans and other species, and has the potential to increase cardiovascular events. Additionally, C. aurantium contains 6′,7′-dihydroxybergamottin and bergapten, both of which inhibit cytochrome P450-3A, and would be expected to increase serum levels of many drugs. There is little evidence that products containing C. aurantium are an effective aid to weight loss. Synephrine has lipolytic effects in human fat cells only at high doses, and octopamine does not have lipolytic effects in human adipocytes.
Microscale synthesis of isotopically labeled 6R-N5, N10 methylene-5, 6, 7, 8-tetrahydrofolate

A one-pot chemo-enzymatic microscale synthesis of isotopically labeled R-[6-YH; 11-XH] N5, N10 methylene-5, 6, 7, 8-tetrahydrofolate (CH2H4folate) is presented, where Y=1 or 2 represents protium or deuterium, and X=1, 2 or 3 represents protium, deuterium or tritium, respectively. In this procedure, Thermoanaerobium brockii alcohol dehydrogenase (tbADH) and Escherichia coli dihydrofolate reductase (ecDHFR) were used simultaneously in the reaction mixture. First, tbADH stereospecifically catalyzes a hydride transfer from [2-YH] iPrOH to the re face of C-4 NADP+. The ecDHFR then reduced 7, 8-dihydrofolate (H2folate) to form (6S)-H4folate. Finally, the enzymatic reactions were followed by chemical trapping with isotopically labeled formaldehyde ([XH]-HCHO) to form the final product. The preparation of deuterium- and tritium-labeled formaldehyde is also presented. Two reverse phase HPLC methods were developed for analysis and purification of product R-[6-YH; 11-XH] CH2H4folate. This isotopically labeled cofactor can be used to study 1° and 2° kinetic isotope effects (KIEs) with any CH2H4folate dependent enzyme as demonstrated by studies with E. coli thymidylate synthase (TS). Copyright © 2005 John Wiley & Sons, Ltd.
Immunosuppressive Therapy and Plasmapheresis in Rapidly Progressive Glomerulonephritis Associated With Bacterial Endocarditis

A 25-year-old male presented with new cardiac murmurs and acute renal insufficiency. Blood cultures grew Streptococcus viridans and appropriate antibiotic therapy was initiated. A renal biopsy revealed diffuse proliferative glomerulonephritis with crescents involving more than 50% of the glomeruli. Treatment with antibiotics, plasmapheresis, and steroids resulted in renal recovery that paralleled reductions in circulating immune complexes. The rationale for this therapeutic approach is discussed, as well as a review of two similar case reports. These experiences suggest a possible role for plasmapheresis and immunosuppressive drugs in patients who develop rapidly progressive glomerulonephritis as a complication of bacterial endocarditis.
Non-mutagenic organic pigment intermediates. II. Isomorphous 2,2'-dichloro-5,5'-dipropoxybenzidine and 2,2'-dimethyl-5,5'-dipropoxybenzidine.

The title compounds, C 18 H 22 Cl 2 N 2 O 2 and C 20 H 28 N 2 O 2 , respectively, are isomorphous. The molecules lie at general positions in the unit cell. In each structure, chemically equivalent but crystallographically inequivalent amine N atoms exhibit different degrees of pyramidalization. The structures exhibit weak N-H...N hydrogen bonding, which is influenced by the differences in hybridization around the amine N atoms. The torsion angles across the biphenyl linkage for the two compounds are 67.2 (2) and 68.3 (3)°.
Catalytic transamidation under moderate conditions

The carboxamide group is generally inert, except under harsh conditions or in the presence of highly evolved enzymes. We have identified several metal complexes that efficiently catalyze transamidation reactions of amide/amine mixtures under moderate conditions. This unprecedented reactivity represents an important step toward our long-term goal of using dynamic combinatorial chemistry to generate new amide-based molecules with interesting structures and functions.
Topical delivery of anti-sense oligonucleotides using low-frequency sonophoresis.

Purpose. Topical delivery of oligonucleotides, though attractive for the treatment of skin disorders, is limited by the low permeability of the stratum corneum. Herein, we assessed the potential of low-frequency ultrasound (20 kHz, 2.4 W/cm2) in delivering therapeutically significant quantities of anti-sense oligonucleotides into skin.
The Genealogy of Student Morals

Nothing is more likely to distort our understanding of reality than the notion of relativism. It was for good reason that Thomas Aquinas began his treatise On Truth by repudiating the “error of the ancient philosophers [Democritus and Protagoras] who said that any opinion a person has in his intellect is true and that two contradictories can be true at the same time. This, of course, is absurd.” Sadly, the relativism that Aquinas deftly dismissed as absurd in the thirteenth century has become the conventional wisdom of our own time, largely because it is so compatible with the assumptions that have shaped modern society: a utilitarian view of reality, a misguided view of the moral authority of popular opinion, and a pragmatic approach to knowledge. The preposterous phrase, “everything is relative,” has long been fixed in the vocabulary of mass culture, and even the Acad. Quest. (2012) 25:257–266 DOI 10.1007/s12129-012-9283-x
Mirex exposure inhibits the uptake of estradiol-17β(β-d-glucuronide), taurocholate, and l-alanine into isolated rat hepatocytes

The insecticides mirex and chlordecone have previously been found to suppress the biliary excretion of a wide variety of compounds. In the present studies, the effects of mirex, chlordecone, and phenobarbital on the uptake of two endogenous organic anions, estradiol-17β(β-d-glucuronide) (E217G), an estrogen metabolite, taurocholate (TC), a common bile acid, and an essential amino acid, l-alanine (l-Ala) (0.5 mm), into isolated rat hepatocytes was investigated. Female Sprague-Dawley rats were orally dosed with mirex (12.5, 25, and 50 mg/kg) or chlordecone (6.25, 12.5, and 18.75 mg/kg) dissolved in corn oil for 3 days and isolated rat hepatocytes were prepared 2 days later. Rats were also dosed orally with phenobarbital (50 mg/kg on the first day and 80 mg/kg for the next 4 days) dissolved in distilled deionized water, and isolated hepatocytes were prepared on the sixth day. Mirex significantly reduced the uptake of both organic anions (0.5, 10, and 50 μm E2 17G; 10 μm TC) into hepatocytes by 40–70%, whereas chlordecone had no effect on their uptake. Mirex at 50 mg/kg significantly reduced the Vmax for the low- and high-affinity E217G uptake sites by 70% and decreased the Km for the low affinity uptake site by 60%. Mirex also significantly decreased the Vmax for TC uptake from 1.11 to 0.82 nmol/min/mg protein but had no effect on its Km (23.2 vs 22.9 μm). Mirex at 50 mg/kg was also found to reduce the uptake of 0.5 mm l-Ala by nearly 40%. Phenobarbital had no effect on the uptake of E217G (0.5 μm), TC (10 μm), or l-Ala (0.5 mm). Mirex treatment had no effect on hepatic plasma membrane Na+,K+- or Mg2+-ATPase activity. Neither mirex nor chlordecone at 50–100 μm had any effect on the uptake of 10 μm TC when added directly to hepatocytes from naive rats. These results indicate that mirex decreases the transport of organic anions and l-Ala across the basolateral domain of the hepatocyte in addition to its inhibitory effects on biliary excretion.