cssi/SciSciGPT-SciSciNet huggingface dataset:
Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution

Before it was molecularly cloned in 1994, acute-phase response factor or signal transducer and activator of transcription (STAT)3 was the focus of intense research into understanding the mammalian response to injury, particularly the acute-phase response. Although known to be essential for liver production of acute-phase reactant proteins, many of which augment innate immune responses, molecular cloning of acute-phase response factor or STAT3 and the research this enabled helped establish the central function of Janus kinase (JAK) family members in cytokine signaling and identified a multitude of cytokines and peptide hormones, beyond interleukin-6 and its family members, that activate JAKs and STAT3, as well as numerous new programs that their activation drives. Many, like the acute-phase response, are adaptive, whereas several are maladaptive and lead to chronic inflammation and adverse consequences, such as cachexia, fibrosis, organ dysfunction, and cancer. Molecular cloning of STAT3 also enabled the identification of other noncanonical roles for STAT3 in normal physiology, including its contribution to the function of the electron transport chain and oxidative phosphorylation, its basal and stress-related adaptive functions in mitochondria, its function as a scaffold in inflammation-enhanced platelet activation, and its contributions to endothelial permeability and calcium efflux from endoplasmic reticulum. In this review, we will summarize the molecular and cellular biology of JAK/STAT3 signaling and its functions under basal and stress conditions, which are adaptive, and then review maladaptive JAK/STAT3 signaling in animals and humans that lead to disease, as well as recent attempts to modulate them to treat these diseases. In addition, we will discuss how consideration of the noncanonical and stress-related functions of STAT3 cannot be ignored in efforts to target the canonical functions of STAT3, if the goal is to develop drugs that are not only effective but safe. SIGNIFICANCE STATEMENT: Key biological functions of Janus kinase (JAK)/signal transducer and activator of transcription (STAT)3 signaling can be delineated into two broad categories: those essential for normal cell and organ development and those activated in response to stress that are adaptive. Persistent or dysregulated JAK/STAT3 signaling, however, is maladaptive and contributes to many diseases, including diseases characterized by chronic inflammation and fibrosis, and cancer. A comprehensive understanding of JAK/STAT3 signaling in normal development, and in adaptive and maladaptive responses to stress, is essential for the continued development of safe and effective therapies that target this signaling pathway.
Ultrafast Self-Assembly of Microscale Particles by Open-Channel Flow

We developed an ultrafast microfluidic approach to self-assemble microparticles in threedimensions by taking advantage of simple photolithography and capillary action of microparticle-dispersed suspensions. The experimental verifications of the assembly of various sizes of silica microspheres and silica gel microspheres within thin and long open microchannels by using this approach have been demonstrated. We anticipate that the presented technique will be widely used in semiconductor and Bio-MEMS (microelectromechanical Systems) fields because it offers a fast way to control 3D, microscale particle assemblies and also has superb compatibility with photolithography, which can lead to an easy integration of particle assembly with existing CMOS (complementary metal-oxide-semiconductor) and MEMS fabrication processes.
An exploration of trends in and predictors of students’ perception of health policy education at a Jesuit medical school

**Background:** Studies have shown an increase in percent of students reporting “adequate” health policy education in medical schools over the past decade. This study identifies which student characteristics—such as race/ethnicity, intended specialty, and plans to work with underserved populations—are associated with reporting “appropriate” vs “inadequate” health policy education at a Jesuit medical institution in the US. **Methods:** Responses from the AAMC Graduation Questionnaire (GQ) for years 2010-2013 to an outcome question evaluating time spent on health policy curriculum were extracted. A multivariable logistic regression analysis was performed to test which student sociodemographic and clinical career training choices impacted satisfaction of health policy education. **Results:** The percent of respondents reporting inadequate time spent on health policy curricula decreased significantly between 2010 and 2013. Students who identified their race/ethnicity as Under-Represented in Medicine were significantly less likely to report appropriate health policy education (OR = 0.419, CI = 0.191-0.919, p=0.03). Other characteristics including male gender, enrollment in a combined degree program, intention to work as university faculty, and intention to serve in an underserved area were also negatively associated with reporting appropriate education; however, these differences were not statistically significant. Furthermore, students in 2013 were significantly more likely to report adequate education compared with those in 2010 (OR = 1.973, CI 1.001-3.891, p = 0.0497). **Conclusions:** While an increasing majority of students report appropriate exposure to health policy education, medical students who are planning to work with underserved populations may still benefit from additional elective education on health policy.
Isolation of Unactuation: An Energetic Approach to Derive Static Equilibria for Underactuated Mechanical Systems.

This paper revisits previous work on nonlinear mechanical control coupling for underactuated mechanical systems (UMS) to study how the coupling can be exploited in system dynamics. When decomposing a velocity field for an UMS into actuated and unactuated directions, the unactuated part can be isolated geometrically, and hence a "programmable" energetic approach is developed to directly obtain static equilibria for the system, instead of using Newton's second law and then eliminating variables. This approach is also interpreted with virtual work analysis. It is applicable to UMS, with any degree of unactuation, or any linkage type. It is also independent of choice of coordinates. A three-link model is adopted to demonstrate the results. Furthermore, a study between coupling and system response among a range of equilibria for an acrobot shows that larger coupling can instantly give more control authority to the unactuated dynamics.
Knockin’ on the Bank’s Door: Why is Self-Employment Going Down?

This study analyzes a decline in the ability to obtain financing as a potential explanation for the observed decrease in the U.S. self-employment. The shrinking of the U.S. bank branch network since 2010 and the increased average borrower-lender distance reduce the accessibility of credit institutions for borrowers. To evaluate the impact of the CMA on entry into self-employment, I disaggregate the self-employed into two categories: entrepreneurs whose businesses depend on business loans (incorporated self-employed) and other self-employed (unincorporated self-employed). Using a novel data source (the Community Advantage Panel Survey database), I find that the proximity of credit market institutions has heterogeneous effects on the transition to self-employment. An improvement in the CMA increases the likelihood of transition to incorporated self-employment. But for the unincorporated self-employed, the effect is the opposite: the probability of transition to unincorporated self-employment decreases, and workers of this type are more likely to switch to paid employment to be able to receive non-business related loans. The paper discusses the implications of these results for different policies.
Risk of in-hospital falls among medications commonly used for insomnia in hospitalized patients.

STUDY OBJECTIVES To investigate the risk of in-hospital falls among patients receiving medications commonly used for insomnia in the hospital setting. METHODS Retrospective cohort study of all adult hospitalizations to a large academic medical center from January, 2007 to July, 2013. We excluded patients admitted for a primary psychiatric disorder. Medication exposures of interest, defined by pharmacy charges, included benzodiazepines, non-benzodiazepine benzodiazepine receptor agonists, trazodone, atypical antipsychotics, and diphenhydramine. In-hospital falls were ascertained from an online patient safety reporting system. RESULTS Among the 225,498 hospitalizations (median age = 57 years; 57.9% female) in our cohort, 84,911 (37.7%) had exposure to at least one of the five medication classes of interest; benzodiazepines were the most commonly used (23.5%), followed by diphenhydramine (8.3%), trazodone (6.6%), benzodiazepine receptor agonists (6.4%), and atypical antipsychotics (6.3%). A fall occurred in 2,427 hospitalizations (1.1%). The rate of falls per 1,000 hospital days was greater among hospitalizations with exposure to each of the medications of interest, compared to unexposed: 3.6 versus 1.7 for benzodiazepines (adjusted hazard ratio [aHR] 1.8, 95%CI 1.6-1.9); 5.4 versus 1.8 for atypical antipsychotics (aHR 1.6, 95%CI 1.4-1.8); 3.0 versus 2.0 for benzodiazepine receptor agonists (aHR 1.5, 95%CI 1.3-1.8); 3.3 versus 2.0 for trazodone (aHR 1.2, 95%CI 1.1-1.5); and 2.5 versus 2.0 for diphenhydramine (aHR 1.2, 95%CI 1.03-1.5). CONCLUSIONS In this large cohort of hospitalizations at an academic medical center, we found an association between each of the sedating medications examined and in-hospital falls. Benzodiazepines, benzodiazepine receptor agonists, and atypical antipsychotics had the strongest associations.
Respiratory Failure in Noonan Syndrome Treated by Microsurgical Thoracic Duct-Venous Anastomosis

Noonan Syndrome is a disorder characterized by central and peripheral lymphatic conducting anomalies, leading to chylothorax, chylous ascites, and metabolic derangement. Novel imaging modalities including dynamic contrast magnetic resonance lymphangiography (DCMRL) and intranodal lymphangiography have allowed for increased visualization of lymphatic pathology. We describe the first study of a 61-year-old male with Noonan syndrome who developed severe pulmonary insufficiency and chylothoraces. DCMRL and intranodal lymphangiography demonstrated central thoracic duct (TD) occlusion. The patient's condition significantly improved following microsurgical TD-venous anastomosis assisted by TD catherization for imaging guidance, resulting in decompression of the lymphatic system and resolution of the pulmonary symptoms.
The Lindbladian form and the reincarnation of Felix Bloch's generalized theory of relaxation

Abstract. The relationship between the classic magnetic resonance density matrix relaxation theories of Bloch and Hubbard and the modern Lindbladian master equation methods are explored. These classic theories are in full agreement with the latest results obtained by the modern methods. A careful scrutiny shows that this also holds true for Redfield's later treatment, offered in 1965. The early contributions of Bloch and Hubbard to rotating-frame relaxation theory are also highlighted. Taken together, these seminal efforts of Bloch and Hubbard can enjoy a new birth of contemporary relevance in magnetic resonance.
Defining clinically important hypoglycemia in patients with postbariatric hypoglycemia

Abstract Background Postbariatric hypoglycemia (PBH) is a rare but growing complication of bariatric surgery. Many aspects have yet to be established, including the blood glucose threshold which represents clinically important hypoglycemia in affected patients. Objective To confirm the glucose threshold below which neuroglycopenic (NG) symptoms arise in patients with PBH during provoked and real-world hypoglycemia as an indicator of clinically important hypoglycemia. Setting Stanford University School of Medicine. Methods Forty patients with PBH were enrolled. Thirty-two patients underwent hypoglycemia provocation in the clinical research unit (CRU) during which symptoms and blood glucose concentrations were assessed. A sensitivity analysis and stepwise linear regression were conducted evaluating relationships between symptoms and glucose levels. To validate CRU findings in the real-world setting, 8 sex-, age-, body mass index (BMI)–, and disease severity–matched patients underwent 20 days of at-home continuous glucose monitoring (CGM), self-monitoring of blood glucose (SMBG), and symptom assessment by electronic diary (eDiary). Results In response to hypoglycemia provocation 19%, 59%, and 22% of patients developed a postprandial glucose nadir Conclusion Due to the peak in NG symptoms at glucose
The SON RNA splicing factor is required for intracellular trafficking structures that promote centriole assembly and ciliogenesis.

The SON RNA splicing factor controls diverse pathways promoting microtubule organization and centriolar satellite formation that support centriole duplication and ciliogenesis.
Effects of infertility, pregnancy loss, and patient concerns on family size of women with rheumatoid arthritis and systemic lupus erythematosus

Objective Women with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have fewer children on average than other women. We sought to determine the roles of infertility, pregnancy loss, and personal choice on family size in women with these diseases. Methods A reproductive history questionnaire was completed by women with RA and SLE participating in a longitudinal observational study. Within each disease cohort, participants were divided into 3 groups: those interested in having children at symptom onset who had either fewer children than planned (group A) or the same number as planned (group B), and those no longer interested in having children at diagnosis (group C). Results Of the 578 RA and 114 SLE women surveyed, >60% were in group C. Of those interested in having children, 55% with RA and 64% with SLE had fewer children than originally planned. Among women with RA, group A had 1 less pregnancy, 1 less live birth, and an infertility rate 1.5 times higher than group B; the miscarriage rate was similar in both groups. Compared to SLE group B, SLE group A had a similar number of pregnancies, but a 3-fold higher rate of miscarriage and 1 less live birth. Concerns about child health and personal welfare were associated with a lower pregnancy rate. Conclusion In this population, more than one-half of young women with RA or SLE had fewer biologic children than desired. While patient choice plays a role, infertility in RA patients and miscarriage in SLE patients are also important.
Macroeconomics in Emerging Markets: The Aggregate Production Function, the Labor Market, and Aggregate Supply

Our next task is to develop an analytical framework – a model – that we can use to think about macroeconomic issues in emerging and developing economies. That will be our objective in Part 2, consisting of this chapter and the four that follow. We will use this model to identify the types of shocks that tend to disrupt short-run macroeconomic stability in those economies, to analyze how such shocks affect a broad range of macroeconomic variables, and to examine the set of instruments that policy makers can potentially deploy to ameliorate the effects of such shocks. We begin that task in this chapter and the next by developing a benchmark version of our model, that is, a simple version to which we will add bells and whistles later on. This chapter and the three that follow build a “short-run” version of this model, in the sense that it holds constant certain important macroeconomic variables that in the real world tend to change very slowly over time. We extend the model to a medium-run setting in Chapter 8 by studying how some of these slowly changing variables evolve over time. The economy that we will begin describing in this chapter has certain features that are worth calling attention to at the outset. First, it is an open economy in the sense that it trades both goods and services as well as financial assets with the rest of the world.
Sensitivity of Long-Standing Xenografts of Rat Hearts to Humoral Antibodies

Long-standing rat skin xenografts on immunosuppressed mice are known to become insensitive to destruction by mouse anti-rat serum. Our present experiments demonstrate that long-standing primarily vascularized rat-to-mouse cardiac xenografts, unlike skin, remain fully sensitive to antiserum-mediated destruction, even in mice also bearing a long-standing skin graft that is resistant to antiserum. It appears that skin grafts become resistant to antiserum-mediated destruction because of extensive replacement of the endothelium by cells of host origin. The hearts remain sensitive to anti-serum since such an extensive endothelial replacement would not occur as readily in these whole organ grafts.
Microcephaly in a Normal School Population

Heights, weights, and head circumferences were obtained on 1,006 students, ages 5 to 18 years, attending regular classes in four schools in a suburban Seattle school district. From the 1,006 students initially examined, 19 (1.9%) had a head circumference two or more standard deviations below the mean for age and sex. Intelligence quotients and academic achievement scores were obtained on these children and compared with normal controls. No significant difference was found between mean IQs of the study subjects and the controls (99.5 vs. 105), but mean academic achievement scores were significantly lower in the study subjects (49 vs. 70; P less than .001). In addition, although mean IQs were not significantly different between those subjects whose head circumference was proportional and those whose head circumference was relatively small, mean academic achievement scores were significantly higher (60 vs 39; P less than .02) in those subjects whose head size was proportional.
Characterization of Pulmonary Arene Oxide Biotransformation Using the Perfused Rabbit Lung

Rapid arene oxide biotransformation has been suggested as a protective mechanism against the effects of polycyclic aromatic hydrocarbons. This is a report on benzo( a )pyrene 4,5-oxide biotransformation by perfused rabbit lungs. Benzo( a )-pyrene 4,5-oxide (5 μmol) was conjugated with glutathione and hydrated at rates of 23.8 ± 2.3 (S.D.) and 7.60 ± 1.14 nmol/min/g of tissue, respectively. The total rate for benzo( a )pyrene 4,5-oxide biotransformation by perfused lungs was about 3 times the estimated rate of arene oxide formation from benzo( a )pyrene found in previous studies. A high-pressure liquid chromatographic system was utilized to resolve the benzo( a )pyrene 4,5-oxide metabolites, which were tentatively identified by cochromatography with compounds of established chemical structure. It was discovered with this chromatographic system that perfused rabbit lungs produce a cysteine conjugate from benzo( a )pyrene 4,5-oxide but lacked the ability to conjugate trans -4,5-dihydro-4,5-dihydroxybenzo( a )pyrene with sulfuric or glucuronic acid at detectable rates. The trans -4,5-dihydro-4,5-dihydroxybenzo( a )pyrene could pass freely from the tissue into the perfusion medium but remained at a relatively high concentration in the lungs, possibly due to the lipophilic nature of this metabolite. The glutathione conjugate, which diffused slowly from the tissue into the perfusion medium, showed no tendency to accumulate in the tissue. Benzo( a )pyrene 4,5-oxide-derived radioactivity was covalently bound to pulmonary DNA, RNA, and protein. The relative activities of toxication/detoxication pathways, the apparent inability of pulmonary tissue to conjugate trans -4,5-dihydroxy-4,5-dihydrobenzo( a )pyrene with sulfuric or β-glucuronic acid, the tendency of some benzo( a )pyrene metabolites to accumulate in the tissue, and the relationship of these parameters with the susceptibility of lung to the effects of polycyclic aromatic are discussed.
Developing Countries Will Follow Post‐crisis OECD Reforms but Not Passively This Time

Will reforms emerging from the 2008 crisis have a global impact and influence developing countries? Evidence suggests that this happened before, after meltdowns in the 1970s. This article deconstructs how reforms diffused in this period and why countries followed different reform timelines. Institutional theory and a descriptive analysis of post-1970s experience suggest that countries followed different reform paths. Developing countries copied reforms seen as legitimate in various OECD countries, supported by entities upon which developing countries were dependent. The article argues that developing countries may not follow the same path now. Endogenous discussions about reform options are more common in developing countries now. More external reform alternatives have also emerged from new development partners such as China, and it is unclear that countries such as the USA will chart postcrisis reform paths developing countries perceive as worthy of following.
CompleteO(αs3)results fore+e−→(γ,Z)→four jets

We present the next-to-leading-order [O({alpha}{sub s}{sup 3})] perturbative QCD predictions for e{sup +}e{sup {minus}} annihilation into four jets. A previous calculation omitted the O({alpha}{sub s}{sup 3}) terms suppressed by one or more powers of 1/N{sub c}{sup 2}, where N{sub c} is the number of colors, and the {open_quotes}light-by-glue scattering{close_quotes} contributions. We find that all such terms are uniformly small, constituting less than 10{percent} of the correction. For the Durham clustering algorithm, the leading and next-to-leading logarithms in the limit of the small jet resolution parameter y{sub cut} can be resummed. We match the resummed results to our fixed-order calculation in order to improve the small y{sub cut} prediction. {copyright} {ital 1997} {ital The American Physical Society}
Choline acetyltransferase-deficient mutants of the nematode Caenorhabditis elegans.

We have identified five independent allelic mutations, defining the gene cha-1, that result in decreased choline acetyltransferase (ChAT) activity in Caenorhabditis elegans. Four of the mutant alleles, when homozygous, lead to ChAT reductions of>98%, as well as recessive phenotypes of uncoordinated behavior, small size, slow growth and resistance to cholinesterase inhibitors. Animals homozygous for the fifth allele retain approximately 10% of the wild-type enzyme level; purified enzyme from this mutant has altered Km values for both choline and acetyl-CoA and is more thermolabile than the wild-type enzyme. These qualitative alterations, together with gene dosage data, argue that cha-1 is the structural gene for ChAT. cha-1 has been mapped to the left arm of linkage group IV and is within 0.02 map unit of the gene unc-17, mutant alleles of which lead to all of the phenotypes of cha-1 mutants except for the ChAT deficiency. Extensive complementation studies of cha-1 and unc-17 alleles reveal a complex complementation pattern, suggesting that both loci may be part of a single complex gene.
Alternative Splicing of a Neural-Specific Src mRNA (Src+) Is a Rapid and Protein Synthesis-Independent Response to Neural Induction in Xenopus laevis

Alternative splicing is used by the src protooncogene to derive two gene products, pp60c-src and pp60+. pp60+ is expressed exclusively in neurons, whereas pp60c-src is expressed in many tissues. The specific role of the src+ gene product in neurons is not yet understood. Expression of src+ mRNA begins early in neural development and is restricted to the neural plate in Xenopus embryos. Using a reverse transcription/polymerase chain reaction assay, we demonstrate that expression of src+ mRNA is dependent on neural induction. Src+ mRNA is expressed in animal cap ectoderm which is cocultured with mesoderm tissue, but not in ectoderm cultured alone. The protein kinase C (PKC) activator 12-O-tetradecanoylphorbol-13-acetate (TPA) induces src+ mRNA expression in cultured stage 10+ animal cap ectoderm. This induction is rapid, with src+ mRNA being detected within 1 hr of TPA addition. Only dorsal ectoderm tissue is competent to express src+ mRNA upon TPA treatment, and stage 10+ ectoderm tissue becomes unresponsive to TPA after 4 hr in culture. TPA-dependent induction of src+ mRNA in ectoderm tissue is not blocked by cycloheximide and therefore is not dependent on protein synthesis.
Multiple leucyl-tRNA synthetases in pea seedlings☆

Abstract Leucyl-tRNA synthetase (LRS) of developing pea seedlings can be separated on hydroxylapatite (HA) columns into two fractions. Freon column chromatography of tRNAs aminoacylated by individual LRS fractions from HA columns indicates that fraction 1 is specific for leucyl-tRNAs 5 and 6 and fraction 2 is specific for tRNAs 1 and 2. Pea epicotyls contain both enzyme fractions. Pea cotyledons have predominantly enzyme fraction 2, whereas leaves have predominantly the first enzyme fraction as well as small amounts of fraction 2. Furthermore, chloroplasts from leaves contain only the first enzyme fraction while the cytoplasm contains predominantly the second LRS fraction.
Methyl‐ccnu, alone and in combination with vincristine, or vincristine and methotrexate, in advanced bronchogenic carcinoma

Ninety-two patients with advanced bronchogenic carcinoma were prospectively randomized according to performance status, histology, and extent of disease to methyl-CCNU alone; methyl-CCNU and vincristine; or methyl-CCNU, vincristine, and methotrexate. Seventy-three patients were evaluable. Randomization to methyl-CCNU alone was discontinued when only three brief "static" responses were noted in 11 patients and the survival (p less than .01) and time on study (p less than .05) were noted to be significantly less than with the combination. Two of 32 patients treated with methyl-CCNU and vincristine, and two of 30 patients treated with methyl-CCNU, vincristine, and methotrexate had mixed responses with a median of 67.5 days. A static response was seen in eight of 32 and none of 30 patients, respectively. Minimal toxicity occurred in all regimens. Methyl-CCNU alone or in combination with vincristine or vincristine and methotrexate is of limited benefit in patients with lung cancer, although our data suggest (p = 0.15) that the addition of methotrexate increases time on study and survival in patients with extensive disease.
Distinct Polyphosphoinositide Binding Selectivities for Pleckstrin Homology Domains of GRP1-like Proteins Based on DiglycineVersus Triglycine Motifs

Abstract GRP1 and the related proteins ARNO and cytohesin-1 are ARF exchange factors that contain a pleckstrin homology (PH) domain thought to target these proteins to cell membranes through binding polyphosphoinositides. Here we show the PH domains of all three proteins exhibit relatively high affinity for dioctanoyl phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3), with KD values of 0.05, 1.6 and 1.0 μm for GRP1, ARNO, and cytohesin-1, respectively. However, the GRP1 PH domain was unique among these proteins in its striking selectivity for PtdIns(3,4,5)P3 versus phosphatidylinositol 4,5-diphosphate (PtdIns(4,5)P2), for which it exhibits about 650-fold lower apparent affinity. Addition of a glycine to the Gly274-Gly275 motif in GRP1 greatly increased its binding affinity for PtdIns(4,5)P2 with little effect on its binding to PtdIns(3,4,5)P3, while deletion of a single glycine in the corresponding triglycine motif of the ARNO PH domain markedly reduced its binding affinity for PtdIns(4,5)P2 but not for PtdIns(3,4,5)P3. In intact cells, the hemagglutinin epitope-tagged PH domain of GRP1 was recruited to ruffles in the cell surface in response to insulin, as were full-length GRP1 and cytohesin-1, but the PH domain of cytohesin-1 was not. These data indicate that the unique diglycine motif in the GRP1 PH domain, as opposed to the triglycine in ARNO and cytohesin-1, directs its remarkable PtdIns(3,4,5)P3 binding selectivity.
Microdialysis sampling extraction efficiency of 2-deoxyglucose: role of macrophages in vitro and in vivo.

Macrophages are a class of inflammatory cells believed to direct the outcome of device biocompatibility. Despite their relevance to implanted in vivo devices, particularly implanted glucose sensors, few studies have attempted to elucidate how these cells affect device performance. Microdialysis sampling probes were used to determine glucose uptake alterations in the presence of resting and activated macrophages in vitro. Significant differences for 2-deoxyglucose (2-DG) relative recovery at 1.0 μL/min were observed between resting (74 ± 7%, n = 18) and lipopolysaccharide (LPS) (1 μg/mL)-activated (56 ± 6%, n = 18) macrophages in culture that had 2-DG spiked into the media (p < 0.005). To establish if in vitro characterization could be correlated to in vivo studies, microdialysis probes were implanted into the dorsal subcutis of male Sprague−Dawley rats for 0, 3, 5, and 7 days. An internal standard, 2-DG, was passed through the microdialysis probe during in vivo studies. No significant differences in 2-DG ...
The effect of fluorination on the bonding of alkyl ethers to the Al(110) surface

Abstract Temperature-programmed desorption (TPD) has been used to investigate the effect of fluorination on the surface chemistry of several model ethers on the Al(110) metal surface. The model compounds studied were dioxolane ( ), diethylether [(CH3CH2)2O], dimethoxymethane [(CH3O)2CH2], dimethylether [(CH3)2O] and their fully fluorinated analogs. Perfluorination of these ethers decreases their desorption energies from ∼13 to ∼7 kcal/mol. At coverages in the range 0.1
Intracellular trafficking of ceramide by ceramide transfer protein.

The transport and sorting of lipids are fundamental to membrane biogenesis. In the synthesis of sphingolipids in mammalian cells, ceramide is newly produced at the endoplasmic reticulum (ER), and transported from the ER to the trans Golgi regions, where it is converted to sphingomyelin. Ceramide transfer protein (CERT) mediates the ER-to-Golgi trafficking of ceramide. It has been suggested that CERT extracts ceramide from the ER and carries it to the Golgi apparatus in a non-vesicular manner and that efficient CERT-mediated trafficking of ceramide occurs at membrane contact sites between the ER and the Golgi apparatus.(Communicated by Kunihiko SUZUKI, M.J.A.)
Redox targeting of LY231617, an antioxidant with potential use in the treatment of brain damage

Abstract Several brain-targeting chemical delivery systems (CDS) based on a dihydropyridine ⇌ pyridinium salt-type targetor were synthesized and evaluated for LY231617 (1), a di-tert-butylated phenolic amine antioxidant with potential use in the treatment of brain injuries. The dihydropyridine moiety was chemically attached to the amine (by either amide or various substituted carbamate linkages) or to the phenolic hydroxyl (by carboxylic ester linkage) functionalities of LY231617. In vitro stability and in vivo tissue distribution studies (in the rat) were performed with the novel derivatives. The results indicated that a simple amide-type CDS demonstrated efficient delivery of LY231617-targetor conjugate to the CNS. This derivative which contains the intact pharmacophore might possess intrinsic pharmacological antioxidant activity. Favorable in vitro properties suggested that a substituted carbamate-type CDS might be a better delivery modality for LY231617.
An Exploration of Some Reliability Results for the Multiscore Depression Inventory

Silmmary.-Data from the Multiscore Depression Inventory and its 10 subscales were analyzed for rest-retest and Kuder-Richardson reliabilities. The test-retest indicated that the generally adequate reliabilities obtained for the scales on the Charleston sample were comparable to those obtained in Chicago. The .71 reliability of the instrumental helplessness subscale, however, was substantially better than that in the previous study, indicating that it may yet be useful as a measure of a relatively stable rather than a uansient construct. The Kuder-Richardson reliabilities increased for nine of the subscales at retest, a result which led to a post hoc analysis implicating both mortality and effects of repeated testing, e.g., memory, consistency motivation, as possible causes of increased consistency. The Multiscore Depression Inventory (Berndt, Petzel, & Berndt, 1980) is a new self-report measure of depression that provides separate scores for 10 subscales as well as a total score for over-all depression. The inventory has demonstrated promising reliability and validity in several recent studies (Berndc, 1980; Berndt & Berndc, in press; Berndt, et al., 1980). In their original article, Berndt, et al. (1980) obtained Kuder-Richardson reliabilities (Kuder & Richardson, 1937) mostly in the mid-.80s for the subscales, and .96 for the full scale. Test-retest reliabilities reported over a 3-wk. interval were also generally adequate, with all but two in the .70s and .80s. The present study attempted initially to replicate the results on a sample from a different geographic region over a comparable time period, as well as exploring immediate retest reliabilities. However, in the course of the investigation we discovered that internal consistency was considerably higher in the retest sample than in the original for some subscales. This observation led to several plausible port hoc explanations. For example, experimental mortality may have accounted for a select sample at the retest which was systematically biased in some way. Another possibility was that subjects retaking the test approached the retest situation with an information-processing bias or set such as a consistency motive (Festinger, 1957; Heider, 1958) . METHOD
Characterization of a neurofilament-associated kinase that phosphorylates the middle molecular mass component of chicken neurofilaments.

Abstract We have examined the properties of a chicken neurofilament (NF) kinase partially purified from NF-enriched preparations. This kinase cosediments with NFs following extraction with Triton X-100 and can be separated in an active form from NFs by treatment with 0.8 M KCl. Sequential chromatography of the salt extract on DEAE-cellulose and phosphocellulose results in an approximately 500-fold increase in specific activity over endogenous NF preparations as measured by32P-incorporation into the middle molecular mass component of NFs (NF-M). The kinase is Mg2+-dependent, second messenger-independent and inhibited by high concentration of heparin. It shows selectivity for NF-M and evidence is presented that the kinase phosphorylates NF-M solely in the tail domain. The kinase can also phosphorylate the microtubule-associated proteins τ and MAP2 as well as mammalian NF-M, all of which share putative phosphorylation sequences with chicken NF-M.
Daylight as a zoning device for midtown

Abstract Since 1960, New York City's Midtown district has experienced an office building boom with the construction of seventy million square feet (650 300 m2) of new office space in one hundred eleven buildings. During this period it became increasingly clear that this new generation of superscale office towers, such as AT & T and IBM, were overpowering their context by dramatically diminishing the daylighting available to the public streets, parks, plazas, and neighboring buildings. The prime cause of this environmental dilemma was the permissive and subjective manner in which the City Planning Commission reviewed Midtown buildings. The waiving of the rigid as-of-right or automatic height and setback regulations for a negotiated review, conceived to encourage good architecture, resulted in daylighting conditions which were measurably worse than those that, in part, led to the call for zoning to protect public access to “light and air” in 1916. The as-of-right zoning regulations which were enacted to guarantee an adequate level of solar access had been superceded by negotiated or discretionary zoning and in the process one of the original goals of zoning was lost. Responding to the defined need for procedural certainty, public accountability, and design and development flexibility, the consultants proposed a performance system of as-of-right zoning based on objective criteria and measurement techniques. The centerpiece of the new building bulk regulations is a modified Waldram Diagram on which the daylighting performance of a building is evaluated against a threshold and standard. The threshold and standard were systematically derived from an analysis of the sixty-year historical expectation for daylight in Midtown. The performance system as adopted by the City is presently being programmed for computer evaluation.
Synthesis of pyrido[1,2-a]benzimidazoles by cyclizative condensation of 2-halopyridines and 1,2-benzenediamines. Scope and mechanism of the reaction

The scope and mechanism of acid-catalyzed cyclizative condensation of 2-halopyridines with 1,2-benzene-diamines has been explored. The reaction requires a 2-halopyridine which is activated toward nucleophilic substitution. Evidence in favor of a mechanism involving pyridine ring opening is presented. Of three substituted 1,2-benzenediamines which were examined, the 4-nitro compound gave a single cyclization product whereas 4-chloro and 4-methy 1-derivatives gave isomeric mixtures. The structure of the product from 2-chloro-5-nitropyridine and 4-nitro-1,2-benzenediamine is shown to be 2,8-dinitropyrido[1,2-a]benz-imidazole.
The diagnosis of proventricular dilatation disease: Use of a Western blot assay to detect antibodies against avian Borna virus

Avian Borna virus (ABV) has recently been shown to be the causal agent of proventricular dilatation disease (PDD) a lethal neurologic disease of captive psittacines and other birds. An immunoblot assay was used to detect the presence of antibodies against avian Borna virus in the serum of affected birds. A lysate from ABV-infected duck embryo fibroblasts served as a source of antigen. The assay was used to test for the presence of antibodies to ABV in 117 birds. Thirty of these birds had biopsy or necropsy-confirmed proventricular dilatation disease (PDD), while the remaining 87 birds were apparently healthy or were suffering from diseases other than PDD. Sera from 27 of the 30 PDD cases (90%) contained antibodies to ABV. Seventy-three (84%) of the apparently ''healthy'' birds were seronegative. Additionally, sera from seven macaws and one parrot trapped in the Peruvian Amazon were seronegative. Positive sera recognized the bornaviral nucleopro- tein (N-protein). While the presence of antibodies to ABV largely corresponded with the development of clinical PDD, 14 apparently healthy normal birds possessed detectable antibodies to ABV. The existence of a carrier state was confirmed when 13 of 15 apparently healthy cockatiels were shown by PCR to have detectable ABV RNA in their feces. Western blot assays may be of significant assistance in diagnosing proventricular dilatation disease. Many apparently healthy birds may however be seronegative while, at the same time, shedding ABV in their feces.
The Nature of Tunneling Pathway and Average Packing Density Models for Protein-Mediated Electron Transfer†

The last 30 years have witnessed the development of increasingly successful theoretical approaches to predicting how a protein's chemical composition and three-dimensional structure influence its propensity to mediate electron-transfer reactions. Analysis has progressed from uniform-barrier models that neglect atomic detail, to pathway models that incorporate the specific nature of the bonding and the protein fold, to multipathway models that add coherently the contributions of pathways, to methods that average over accessible geometries. Large-scale electronic structure methods remain of somewhat limited use because: the demands of geometry sampling and electronic structure calculation are considerable, especially for slower ET events; qualitative new insights arising from the more intensive analysis have been moderate; and structure−function relations become increasingly difficult to derive from more complex models. For these reasons, simple models remain both useful and popular. The simplest structure...
IR Fiber Mid-IR Raman Amplifier

We demonstrate mid-IR Raman amplification at 4.6 µm in As2S3 fiber. ~15 dB of amplification and 24% power conversion was achieved in a 3.5 meter fiber length.
Heterogeneity generation by thermodiffusional mechanism in rapidly solidified amorphous alloys

Rapid solidification can produce amorphous alloys and materials with homogeneous and microcrystalline structures. However, chemical, structural, topological and other heterogeneities are frequently observed in rapidly solidified materials. Chemical macro-heterogeneity in melt-spun amorphous alloys is considered in this paper. In binary amorphous alloys (i.e. binary glass metals), it is expressed in rising of metalloid content from the contact side to the free surface side of the melt spun ribbon. The thermodiffusional mechanism of this heterogeneity generation is investigated. A mathematical model of the melt-spinning process was developed and numerically calculated for the case of binary alloys. Simulation of the process showed that the concentration wave appears in the liquid alloy film during its quenching. This wave moves from the contact surface to the free surface, and the concentration heterogeneity is developed before the solidification begins. The amplitude of heterogeneity strongly depends on the thermo-physical properties of the material and the process parameters. The simulation results compare favorably with the experimental observation using X-ray spectral microanalysis.
Specific fractionation and manipulation of lymphocytes with derivatized nylon fibers

Abstract Antigen-coated nylon fibers have been used to fractionate and manipulate specific antigen-binding lymphocytes. Using this system, it has been possible to determine the frequency, specificity and affinity of these cells for a variety of antigens, and to isolate and characterize antigen-specific T or B cells. An in vivo transfer system has been used to demonstrate that the fractionated B cells are highly enriched in specific precursors of antibody-secreting cells. Experiments comparing the morphology, motility and immunoglobulin receptors of lymphocytes bound to antigen- or concanavalin A-coated fibers indicate that interaction of local areas on the cell surface with specific fiber-bound ligands can alter the behavior of the entire cell. These experiments serve to demonstrate the sensitivity and versatility of antigen-coated fibers in isolating and characterizing lymphoid cell populations. The ability to visualize and manipulate individual cells also suggests that this method can be used for a variety of studies on molecule-cell and cell-cell interactions in the immune response.
An onboard star identification algorithm

The paper presents the autonomous Initial Stellar Acquisition (ISA) algorithm developed for the X-Ray Timing Explorer for prividing the attitude quaternion within the desired accuracy, based on the one-axis attitude knowledge (through the use of the Digital Sun Sensor, CCD Star Trackers, and the onboard star catalog, OSC). Mathematical analysis leads to an accurate measure of the performance of the algorithm as a function of various parameters, such as the probability of a tracked star being in the OSC, the sensor noise level, and the number of stars matched. It is shown that the simplicity, tractability, and robustness of the ISA algorithm, compared to a general three-axis attiude determination algorithm, make it a viable on-board solution.
Collagen-Hyaluronic Acid Hydrogels Provide Enhanced EMT of Endocardial Cells

A viable tissue engineered heart valve (TEHV) replacement would eliminate disadvantages associated with currently available prosthetics, such as thrombosis and increased risk of valve calcification. Viable TEHVs also are promising in that they can actively remodel and grow, as they would be populated with cells similar to native valves. Valvular interstitial cells (VICs) organize and maintain the complex structure of valves throughout the life of an organism. Considerable effort has been made towards identifying a source of VICs for next generation prosthetic heart valves. Despite this effort, the mechanisms by which VICs are produced in development, via endocardial epithethelial-to-mesenchymal transformation (EMT), are not fully understood. EMT is the critical first step in the formation of heart valve leaflets in utero, and thus a thorough understanding of the biomechanical and signaling environments that regulate EMT could lead to advancements in viable TEHVs.Copyright © 2013 by ASME
Resolution in the receptor binding of putative μ and κ opiates

Conditions for the stereospecific binding of 3H-ethylketocyclazocine and 3H-etorphine were established in membranes from rat and pigeon brain. In displacing the specific binding of the radiolabeled ligands, putative mu and kappa opiates displayed different sensitivity toward sodium. In membranes from both species, the ratio of the sodium responses exhibited by a given drug in displacing 3H-ethylketocyclazocine and 3H-etorphine, respectively, ("double sodium ratio" = DSR) distinguished between mu and kappa opiates. Compounds characterized on the basis of their pharmacological effects as kappa opiates had DSR values between 0.3 and 2.2, regardless of their nature as agonists or antagonists. In contrast, the DSR for mu opiates ranged from 3.4 to 11. In rat brain membranes, UM 1382 (U-50,488, a compound with pronounced kappa activity) exhibited a DSR of 0.3, while the corresponding value for morphine was 7.4. Dynorphin-(1-13) had a DSR of 1. Within each of the two groups, the simple sodium ratio continued to serve as an index for the agonist or antagonist property of the tested opiates.
Prognostic factors for recurrence following negative second-look laparotomy in ovarian cancer patients treated with platinum-based chemotherapy

Abstract Prior studies of the risk of recurrence following negative second-look laparotomy have included patients treated with a variety of chemotherapeutic regimens, including nonplatinum regimens. We have examined the long-term outcome and risk factors for recurrence among a homogeneous group of platinum-treated patients. During the years 1978–1987, 91 patients at Memorial Sloan-Kettering Cancer Center had a negative second-look laparotomy following platinum-based chemotherapy for epithelial ovarian cancer. The mean age at diagnosis was 57 years, with a range of 30 to 79. Distribution by stage was as follows: I, 10; II, 18; III, 57; IV, 6. The mean number of cycles of platinum prior to second-look surgery was 6.3. The mean number of biopsies taken at negative second-look laparotomy was 12. Lymph node biopsies were done in 4791 (52%) of patients. Median follow-up from the date of second-look laparotomy was 54.6 months among survivors. Forty of ninety-one patients (44%) have had recurrence, almost 40% of which were outside the peritoneal cavity. The mean interval from negative second-look laparotomy to recurrence was 24 months (range, 2–70 months). By multivariate analysis the risk of recurrence was significantly related to stage ( P = 0.017), histologic grade ( P = 0.041), and the amount of tumor remaining after the first operation for ovarian cancer ( P = 0.015). Recurrence by stage was as follows: stage I, 110 (10%); stage II, 518 (28%); stage III, 3157 (54%); stage IV, 36 (50%). Recurrence by grade was as follows: grade 1, 418 (22%); grade 2, 1128 (39%); grade 3, 2545 (56%). There was no relationship between the risk of recurrence and the number of cycles of platinum, the number of biopsies performed at second-look, or the number of months from primary surgery to second-look. Patients having negative second-look laparotomy following platinum-based chemotherapy for advanced epithelial ovarian cancer have a substantial risk of recurrence, particularly within the first 3 years. Such patients should be offered participation in clinical trials of consolidation therapy directed against both intraperitoneal and extraperitoneal disease.