cssi/SciSciGPT-SciSciNet huggingface dataset:
Early in vivo infection dynamics in non-human primates infected with Mycobacterium tuberculosis (MPF3P.813)

Tuberculosis (TB) continues to pose a significant health risk to morbidity and mortality worldwide. The vast majority of individuals infected with M. tuberculosis , the causative agent of TB, contain the infection as clinically asymptomatic latent TB. A small minority of people do not and either present with primary active disease or reactivate over their lifetime. By examining early events in infection at the local lesion level, we aim to uncover some of the basis for the observed spectrum of TB disease and host outcome. Using genetically barcoded M. tuberculosis , serial PET/CT lesion imaging, and tools to analyze each granuloma at the microbial and immunological level, we are tracking local lesion development and dissemination at various stages of infection in cynomolgus macaques. Background studies have revealed that granulomas are dynamic entities that largely arise from single bacteria. We hypothesize that early interactions between M. tuberculosis and host immune components contribute to lesion heterogeneity and that these initial events influence infection outcome. We performed a small reinfection experiment with M. tuberculosis barcoded strains. Our data suggests that primary infection limits secondary infection lesion development and dissemination. Further analysis of this study is ongoing. Probing the mechanisms that underlie the human TB spectrum will reveal crucial stages of infection that can be exploited for novel therapeutic design.
Serum concentrations of luteinizing hormone, growth hormone, testosterone, estradiol, and leptin in boars treated with n-methyl-D,L-aspartate.

Three experiments were conducted to determine the effects of n-methyl-D,L-aspartate (NMA), an agonist of the excitatory amino acid glutamate, on secretion of hormones in boars. In Exp. 1, boars (185.0+/-.3 d of age; mean +/- SE) received i.v. injections of either 0, 1.25, 2.5, 5, or 10 mg of NMA/kg BW. There were no effects of NMA (P>.1) on secretion of LH and testosterone. Treatment with NMA, however, increased (P .1), increased serum concentrations of LH (P .1) on circulating concentrations of estradiol or leptin; however, estradiol concentrations increased (P<.03) with age. In summary, NMA increased secretion of LH, GH, and testosterone in boars. However, endocrine responses to treatment with NMA may be influenced by age of the animal. Finally, NMA did not influence circulating concentrations of estradiol or leptin.
Error Analysis of the Kmetz/Maenner Algorithm

Use of low-precision logarithms can minimize power consumption and increase the speed of multiply-intensive signal-processing systems, such as FIR filters. Although straight table lookup is the most obvious way to compute the logarithm, Maenner claims to have discovered a technique that produces four extra bits at no cost. We analyze Maenner's technique and show that in fact the technique provides only one extra bit of precision. A related technique by Kmetz, which has never been analyzed before, is shown here to be more accurate than Maenner's. We compare these techniques to the more complex bipartite technique, and show that Kmetz's technique takes less memory for systems requiring fewer than ten bits of precision.
Chronic myelomonocytic leukemia: 2013 update on diagnosis, risk stratification, and management

Disease overview Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder that is classified as a myelodysplastic/myeloproliferative neoplasm by the 2008 World Health Organization classification of hematopoietic tumors. It is characterized by absolute monocytosis (>1 × 109/L) in the peripheral blood that persists for at least 3 months. Diagnosis The diagnosis of CMML rests on a combination of morphologic, histopathologic and chromosomal abnormalities in the bone marrow. It is important to exclude other myeloproliferative neoplasms and infectious/autoimmune conditions that can cause monocytosis. Risk stratification Several CMML-specific prognostic models incorporating novel mutations have been recently reported. The Mayo prognostic model classified CMML patients into three risk groups based on: increased absolute monocyte count, presence of circulating blasts, hemoglobin 65 years, WBC >15 × 109/L, anemia, platelets <100 × 109/L, and ASXL1 mutation status. After a median follow-up of 2.5 years, survival ranged from not reached in the low-risk group to 14.4 months in the high-risk group. Risk-adapted therapy The Food and Drug Administration has approved azacitidine and decitabine for the treatment of patients with CMML. An allogeneic stem cell transplant can potentially offer a curative option to a subset of CMML patients. It is hoped that with the discovery of several novel mutations, targeted therapies will become available in the near future. Am. J. Heamtol. 88:968–974, 2013. © 2013 Wiley Periodicals, Inc.
Domain Specificity and Intuitive Ontology.

Traditionally, psychologists have assumed that people come equipped only with a set of relatively domain-general faculties, such as “memory” and “reasoning,” which are applied in equal fashion to diverse problems. Recent research has begun to suggest that human expertise about the natural and social environment, including what is often called “semantic knowledge”, is best construed as consisting of different domains of competence. Each of these corresponds to recurrent evolutionary problems, is organised along specific principles, is the outcome of a specific developmental pathway and is based on specific neural structures. What we call a “human evolved intuitive ontology” comprises a catalogue of broad domains of information, different sets of principles applied to these different domains as well as different learning rules to acquire more information about those objects. All this is intuitive in the sense that it is not the product of deliberate reflection on what the world is like. This notion of an intuitive ontology as a motley of different domains informed by different principles was first popularised by developmental psychologists (R. Gelman, 1978; R. Gelman & Baillargeon, 1983) who proposed distinctions between physical-mechanical, biological, social and numerical competencies as based on different learning principles (Hirschfeld & Gelman, 1994). In the following decades, this way of slicing up semantic knowledge received considerable support both in developmental and neuro-psychology. For example, patients with focal brain damage were found to display selective impairment of one of these domains of knowledge to the exclusion of others (Caramazza, 1998). Neuroimaging and cognitive neuroscience are now adding to the picture of a
The Multiple Faces of Effective Grand Strategy

Effective national leaders throughout history have deliberately developed grand strategies and successfully implemented them to attain their political goals, while also integrating and accomplishing economic, social, defense, and sometimes religious objectives. Not all leaders have been successful, however, as this process is immensely complex and can be adversely affected by the actions of other leaders around their region and the world. It bears examination, then, to determine what factors contribute to successful grand strategies and why many leaders fail to reach their stated ends. This article utilizes a historic case study approach and explores three key areas of grand strategy: universal principles, Clausewitzian approaches, and indirect approaches. I handle each separately and in distinct fashion, though some connective tissue does interlace across sections. Additionally, the unifying argument is that thoughtful, rational leaders, who weigh the costs and benefits associated with each course of action available to them, still must heed the truths embedded in these three sections to attain their objectives. Not doing so often leads to failure, unrealized goals, and a nation gone awry. This article is available in Journal of Strategic Security: http://scholarcommons.usf.edu/jss/vol3/iss2/1 1 The Multiple Faces of Effective Grand Strategy
Evaluation of Drought Indices Based on Thermal Remote Sensing of Evapotranspiration over the Continental United States

AbstractThe reliability of standard meteorological drought indices based on measurements of precipitation is limited by the spatial distribution and quality of currently available rainfall data. Furthermore, they reflect only one component of the surface hydrologic cycle, and they cannot readily capture nonprecipitation-based moisture inputs to the land surface system (e.g., irrigation) that may temper drought impacts or variable rates of water consumption across a landscape. This study assesses the value of a new drought index based on remote sensing of evapotranspiration (ET). The evaporative stress index (ESI) quantifies anomalies in the ratio of actual to potential ET (PET), mapped using thermal band imagery from geostationary satellites. The study investigates the behavior and response time scales of the ESI through a retrospective comparison with the standardized precipitation indices and Palmer drought index suite, and with drought classifications recorded in the U.S. Drought Monitor for the 2000–0...
Prospects for a big idea - is there a future for convergence?

(2003). Prospects for a big idea ‐ is there a future for convergence? International Journal on Media Management: Vol. 5, No. 1, pp. 7-11.
Clinical challenges in the management of vaginal prolapse

Pelvic organ prolapse is highly prevalent, and negatively affects a woman's quality of life. Women with bothersome prolapse may be offered pessary management or may choose to undergo corrective surgery. In choosing the most appropriate surgical procedure, there are many factors to consider. These may include the location(s) of anatomic defects, the severity of prolapse symptoms, the activity level of the woman, and concerns regarding the durability of the repair. In many instances, women and their surgeons are challenged to weigh the risks and benefits of native tissue versus mesh-augmented repairs. Though mesh-augmented repairs may offer better durability, they are also associated with unique complications, such as mesh erosion. Furthermore, newer surgical techniques of mesh placement via abdominal or vaginal routes may result in different outcomes compared to traditional techniques. Biologic grafts may also be considered to improve durability of a surgical repair, while avoiding potential complications of synthetic mesh. In this article, we review many of the clinical challenges that gynecologic surgeons face in the surgical management of vaginal prolapse. Furthermore, we review data that can help guide decision making when treating women with pelvic organ prolapse.
The STONE score can help diagnose urolithiasis and decrease the use of CT scans

Commentary on : Moore CL, Bomann S, Daniels B, et al. Derivation and validation of a clinical prediction rule for uncomplicated ureteral stone—the STONE score: retrospective and prospective observational cohort studies. BMJ 2014;348:g2191.[OpenUrl][1][Abstract/FREE Full Text][2] In the USA, symptomatic nephrolithiasis leading to flank or kidney pain is responsible for over two million annual visits to the emergency department, amounting to a burden on the country's healthcare system of over $5 billion (£3 billion) annually.1 CT is the most accurate imaging modality for the evaluation of suspected acute renal colic due to its superior sensitivity and specificity for detection of renal and ureteral stones.2 However, CT scans also come with a greater exposure to potentially harmful ionising radiation (as well as increased cost). In this manuscript, the authors derive and validate an objective clinical prediction … [1]: {openurl}?query=rft.jtitle%253DBMJ%26rft_id%253Dinfo%253Adoi%252F10.1136%252Fbmj.g2191%26rft_id%253Dinfo%253Apmid%252F24671981%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=ABST&journalCode=bmj&resid=348/mar26_2/g2191&atom=%2Febmed%2F19%2F6%2F234.atom
Rhetorical Hiccups: Disability Disclosure in Letters of Recommendation

This article positions letters of recommendation as important and troubling indicators of faculty beliefs about diversity and access in higher education. I focus on the disclosure of disability, both by examining the history of disclosing stigmatized difference and by analyzing five letters of recommendation for an aspiring graduate student with a traumatic brain injury. I suggest that faculty must revise their letter-writing practices and engage in a type of rhetorical forecasting that questions well-intentioned disclosures of difference and imagines how various letters form a composite sketch of a candidate.
Suppression of MicroRNA-9 by Mutant EGFR Signaling Upregulates FOXP1 to Enhance Glioblastoma Tumorigenicity

The EGF receptor (EGFR) is amplified and mutated in glioblastoma, in which its common mutation (ΔEGFR, also called EGFRvIII) has a variety of activities that promote growth and inhibit death, thereby conferring a strong tumor-enhancing effect. This range of activities suggested to us that ΔEGFR might exert its influence through pleiotropic effectors, and we hypothesized that microRNAs might serve such a function. Here, we report that ΔEGFR specifically suppresses one such microRNA, namely miR-9, through the Ras/PI3K/AKT axis that it is known to activate. Correspondingly, expression of miR-9 antagonizes the tumor growth advantage conferred by ΔEGFR. Silencing of FOXP1, a miR-9 target, inhibits ΔEGFR-dependent tumor growth and, conversely, de-repression of FOXP1, as a consequence of miR-9 inhibition, increases tumorigenicity. FOXP1 was sufficient to increase tumor growth in the absence of oncogenic ΔEGFR signaling. The significance of these findings is underscored by our finding that high FOXP1 expression predicts poor survival in a cohort of 131 patients with glioblastoma. Collectively, these data suggest a novel regulatory mechanism by which ΔEGFR suppression of miR-9 upregulates FOXP1 to increase tumorigenicity.
Blind Spot: When Journalists Don't get Religion

Marshall, P., Gilbert, L., & Ahmanson, R. G. (Eds.). (2009). New York: Oxford University Press, 220 pp., $99.00 (hardcover). It seems as if today everyone has a complaint about the way journalists ...
Convergence of functions of operators in the strong operator topology

In this note, we show that if a net /Q(T) converges pointwise to /(T), then there is a subsequence /Q.M uniformly convergent to / on the compact subsets of some part of the spectrum of T. This extends a well known result in the case of uniform convergence of functions of operators. We give some applications of the result.
Coupled long-range carbon-hydrogen correlation experiment without refocusing delay

Abstract In long-range carbon-hydrogen correlation experiments with standard heteronuclear shift correlation sequences cross-peak intensities can be severely attenuated due to modulation by “interfering” long-range couplings with other protons. Often cross peaks, even if the polarization transfer delay, Δ1, is optimized, can be missed due to the wrong choice of the refocusing delay, Δ2. A useful improvement is to eliminate the Δ2 delay and acquire without proton decoupling. A one-step low-pass J filter is introduced before evolution to suppress one-bond correlations and this sequence is compared to decoupled versions (the standard heteronuclear shift correlation sequence and the COLOC sequence with one-step low-pass J filter before evolution and a BIRD pulse midway through Δ2). Using rotenone as an example we show the advantages of removing the “refocusing” (“defocusing”) delay and retaining 1H coupling in the F2 dimension. It is suggested that the decrease in S/N (by a factor of 2 or less) is often not very significant compared to the danger of accidental missing of cross peaks due to the wrong choice of Δ2.
The adsorption of CO and O2 on Ni(111) at 8 K

The adsorption of CO and O2 on Ni(111) at 8 K is studied by molecular beam techniques coupled with high resolution electron energy loss spectroscopy and work function measurements. The work functions are measured by a retarding potential technique using the HREEL spectrometer. The cryogenic crystal temperatures are attained by use of a liquid helium cryostat described in detail. The total and normal components of the translational energy of the incident molecules are lowered to 0.3 and 0.02 kcal mol−1, respectively. No evidence for a trapped, physisorbed CO molecule or a physisorbed molecular O2 species is observed in the limit of zero coverage.
Quantum chemical investigation of low-temperature intramolecular hydrogen transfer reactions of hydrocarbons.

The B3LYP functional was evaluated as a method to calculate reaction barriers and structure-reactivity relationships for intramolecular hydrogen transfer reactions involving peroxy radicals. Nine different basis sets as well as five other MO/DFT and hybrid methods were used in comparing three reactions to available experimental data. It was shown that B3LYP/6-311+G(d,p) offers a good compromise between speed and accuracy for studies in which thermodynamic and kinetic data of many reactions are required. Sixteen reactions were studied to develop structure-reactivity relationships to correlate the activation energy with the heat of reaction. As long as no structural heterogeneities were present in the transition state ring, a simple Evans-Polanyi relationship was shown to capture the activation energy as a function of heat of reaction for reactions in the 1,5-hydrogen shift family. For peroxy radicals undergoing self-abstraction of a hydrogen atom in the 1,5-position, the activation energy was calculated as E(a) (kcal mol(-1)) = 6.3 + Delta H(rxn) (kcal mol(-1)). For reactions with a carbonyl group embedded in the ring of the transition state, the activation energy of peroxy radicals undergoing self-abstraction was correlated as E(a) (kcal mol(-1)) = 18.1 + 0.74 Delta H(rxn) (kcal mol(-1)). The impact of the size of the transition state ring on the activation energy and pre-exponential factor was also probed, and it was shown that these effects can be described using simple nonlinear and linear fits, respectively.
Matrix metalloproteinase-2 or -9 deletions protect against hemorrhagic transformation during early stage of cerebral ischemia and reperfusion

MMP-9 deficiency protected against photochemical thrombosis-induced brain hemorrhagic transformation (HT), but it did not protect against tissue plasminogen activator-induced brain hemorrhage. The roles of MMP-2 and/or MMP-9 knockout (KO) in mechanical reperfusion induced HT after ischemia have not been investigated. Here we assessed the effects of MMP-2 KO, MMP-9 KO and MMP-2/9 double KO (dKO) in protecting against mechanical reperfusion induced HT and other brain injuries after the early stages of cerebral ischemia in mice of the same genetic background. Middle cerebral artery occlusion (MCAO) was performed in mice. Reperfusion was started at 1 or 1.5h after onset of MCAO. All mice were sacrificed 8h after MCAO. We found that both pro- and active MMP-2 and MMP-9 levels were significantly elevated in the early ischemic brain. After the early stages of ischemia and reperfusion, the hemorrhagic incidence was reduced in the cortex of MMP-2 KO mice (p<0.05 vs. WT). The hemorrhagic volume was significantly decreased in the cortexes of MMP-2 and/or -9 knockout mice (MMP-9 KO vs. WT: p<0.01, MMP-2 KO and dKO vs. WT: p<0.001). In the basal ganglia, MMP-2 KO and MMP-2/9 dKO mice displayed a remarkable decrease in hemorrhagic volume (p<0.01 or 0.05 vs. WT), but MMP-9 KOs did not protect against hemorrhage. MMP-2 and/or -9 knockout mice displayed significantly decreased infarction volume in both the cortex and striatum, in addition to improved neurological function (p<0.001 vs. WT). The results suggested that MMP-2 deficiency and MMP-2 and MMP-9 double deficiency were more protective than MMP-9 deficiency against HT after the early stages of ischemia and reperfusion. These studies increase our understanding of MMP-2 and MMP-9 in HT development and will help to selectively target MMPs to protect the post-ischemic brain from injury and HT.
Epidermal growth factor and transforming growth factor-α enhance the interleukin-1- and tumor necrosis factor-stimulated prostaglandin E2 production and the interleukin-1 specific binding on amnion cells

Abstract Interleukin-1 (IL-1), tumor necrosis factor (TNF), epidermal growth factor (EGF), and transforming growth factor-α (TGF-α) stimulate prostaglandin E 2 (PGE 2 ) production by amnion cells whereas TGF-β inhibits the PGE 2 production. During labor occurring in the setting of infection, several of these cytokines may be simultaneously present in amniotic fluid. The aim of the present study was to examine whether these cytokines modify each others' effects on amnion cell PGE 2 production. Amnion cells in monolayer culture were treated with IL-1, TNF, EGF, TGF-α, TGF-β1, their combination, or vehicle. The PGE 2 production and the specific binding of radiolabeled IL-1β on the cells were measured. IL-1 or TNF in combination with EGF or TGF-α stimulated synergistically the production of PGE 2 by amnion cells. TGF-β1 did not modify the PGE 2 -stimulatory effect of EGFTGF-α. Untreated amnion cells expressed 1030 ± 100 IL-1β receptors per cell with a binding affinity of 1.40 ± 0.26 nM. Treatment with TGF-α increased the number of receptors to 3940 ± 260 per cell with no change in binding affinity. The potentiation of the PGE 2 -stimulatory effect of IL-1 by TGF-α may be related to its ability to induce IL-1 receptors on amnion cells. The synergistic effects of cytokines on amnion cell PGE 2 production may promote labor.
Atmospheric turbulence analysis with the Keck adaptive optics systems

The wavefront sensors of adaptive optics systems of astronomical telescopes collect an abundance of high temporal resolution information about the distortions that are introduced to the incoming wavefront by atmospheric turbulence. Although this information can theoretically be used to analyze the turbulence conditions above the telescope at the given time, it is often discarded. The reason for this dismissal of seemingly useful information is usually the difficulty of separating atmospheric and instrumental contributions to the wavefront sensor measurements and thus of obtaining reliable estimates of the atmospheric turbulence conditions. In this paper we describe an effort to overcome these problems for wavefront sensor measurements taken by the Keck telescopes on Mauna Kea. We discuss different methods of deriving turbulence parameters, such as coherence length and time and the outer scale of turbulence, and present first results.
Stopping times for stochastic approximation procedures

The pioneering paper in the field of stochastic approximation was published in 1951 by Robbins and Monro [6]. That paper dealt with the following situation. Suppose that, for every point x belonging to the real line, a random variable Y(x) can be observed. The distribution function of Y(x) and the expected value of Y(x), denoted by M(x) and assumed to exist, are both unknown. Assuming that the equation M(x)=~ has a unique root, denoted by x = 0, it is desired to estimate 0 by making observations on Y at points x 1, xz, x3, ... which are generated sequentially in accordance with some definite experimental procedure in such a way that x ,~O in probability as n~oo. The Robbins-Monro procedure (RM) for generating the sequence {x,} is to take x I to be any constant and define Xz, x3, ... in accordance with the recurrence
Progesterone Is Not Responsible for the Blood Pressure Fall in Late-Pregnant New Zealand Genetically Hypertensive Rats

In various models of experimental and genetic hypertension in rats, blood pressure is markedly reduced during late pregnancy. The period during which the blood pressure reduction occurs is also the period when plasma progesterone is maximally elevated, and administration of progesterone to renal hypertensive rats has been reported to reduce blood pressure (J. Armstrong, 1959, Proc. Soc. Exp. Biol. Med. 102:452-455). To test the possibility that elevated plasma progesterone is responsible for the blood pressure reduction in late pregnancy, on Day 14 of pregnancy a group of New Zealand genetically hypertensive (NZGH) rats was ovariectomized and implanted with progesterone-filled capsules, to maintain plasma progesterone at low levels just sufficient to maintain pregnancy, and compared with intact, pregnant NZGH. Ovariectomy did not alter the characteristic course of blood pressure reduction seen in late-pregnant intact NZGH rats. In addition, daily administration of progesterone (15 mg/kg, sc) for 14 days did not alter blood pressure of either nonpregnant NZGH rats or New Zealand normotensive rats with chronic 1-kidney, 1-clip hypertension. It is concluded that blood pressure of NZGH rats is reduced to near normotensive levels in late pregnancy, as reported for other models of rat hypertension, but that elevated plasma progesterone levels are not requisite for that reduction and do not reduce blood pressure of renal hypertensive rats.
Plasma Prohormone Atrial Natriuretic Peptides 1-98 and 31-67 Increase with Supraventricular and Ventricular Arrhythmias

Recently two peptides consisting of amino acids (AA) 1-30 and 31-67 of the N-terminus of the 126 AA prohormone of atrial natriuretic factor (pro ANF) as well as atrial natriuretic factor (ANF, AA 99-126; C-terminus) were found to have vasodilatory and natriuretic properties. These peptides as well as ANF circulate in man as part of the N-terminus of the prohormone. To determine if the polyuria, associated with both ventricular and supraventricular arrhythmias, is associated with increased circulating concentrations of the N-terminus and C-terminus of the ANF prohormone, 20 individuals with spontaneous arrhythmias, including ten persons with atrial fibrillation, six with paroxysmal supraventricular tachycardia, and four with ventricular tachycardia, were evaluated before and after conversion to sinus rhythm. In all 20 patients, the circulating concentrations of the whole N-terminus (ie, AA 1-98), the midportion of the N-terminus (pro ANF 31-67) that circulates as a distinct 3900 molecular weight peptide after being proteolytically cleaved from the N-terminus, and the C-terminus were significantly higher (p less than 0.001) than their concentration in 54 persons with sinus rhythm. With conversion to sinus rhythm, the plasma C-terminus concentration of these 20 arrhythmia patients decreased to the level of persons with sinus rhythm within 30 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)
Requirement of IFI16 for the Maximal Activation of p53 Induced by Ionizing Radiation

IFI16 is a member of the PYRIN superfamily that has been implicated in BRCA1-mediated apoptosis and inflammation signaling pathways. Here we report that most breast cancer cell lines examined expressed decreased mRNA and protein levels of IFI16, although IFI16 is expressed in human primary normal mammary epithelial cells. Significantly, immunohistochemical analysis of tissues from 25 breast cancer patients demonstrated that carcinoma cells showed negative or weaker staining of IFI16 compared with positive nuclear staining in normal mammary duct epithelium. si-RNA-mediated reduction of IFI16 resulted in perturbation of p53 activation when treated with ionizing radiation (IR). Expression of IFI16 enhanced p53 transcriptional activity in cells exposed to IR. Adenovirus expression of IFI16 in IFI16-deficient MCF7 induced apoptosis, which was enhanced by radiomimetic neocarcinostatin treatment. Tetracycline-regulated IFI16 also induced apoptosis when coexpressed with p53 in p53-deficient EJ cells subjected to IR, suggesting that IFI16 is involved in p53-mediated transmission of apoptosis signaling. Consistent with these results, expression of IFI16 enhanced activation of the known p53 target genes, including p21, Hdm2, and bax in MCF7 cells. These results suggest that loss of IFI16 results in deregulation of p53-mediated apoptosis, leading to cancer development.
Development of allosteric modulators of GPCRs for treatment of CNS disorders

Abstract The discovery of allosteric modulators of G protein-coupled receptors (GPCRs) provides a promising new strategy with potential for developing novel treatments for a variety of central nervous system (CNS) disorders. Traditional drug discovery efforts targeting GPCRs have focused on developing ligands for orthosteric sites which bind endogenous ligands. Allosteric modulators target a site separate from the orthosteric site to modulate receptor function. These allosteric agents can either potentiate (positive allosteric modulator, PAM) or inhibit (negative allosteric modulator, NAM) the receptor response and often provide much greater subtype selectivity than orthosteric ligands for the same receptors. Experimental evidence has revealed more nuanced pharmacological modes of action of allosteric modulators, with some PAMs showing allosteric agonism in combination with positive allosteric modulation in response to endogenous ligand (ago-potentiators) as well as “bitopic” ligands that interact with both the allosteric and orthosteric sites. Drugs targeting the allosteric site allow for increased drug selectivity and potentially decreased adverse side effects. Promising evidence has demonstrated potential utility of a number of allosteric modulators of GPCRs in multiple CNS disorders, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, as well as psychiatric or neurobehavioral diseases such as anxiety, schizophrenia, and addiction.
Antiepiligrin cicatricial pemphigoid. A subepithelial bullous disorder

Background: Epiligrin is a glycoprotein complex deposited in extracellular matrix by cultured human keratinocytes that serves as the major integrin ligand of these cells. In human skin, epiligrin is found at the interface of the lamina lucida and lamina densa in epidermal basement membrane where it is believed to be associated with anchoring filaments and plays an important role in keratinocyte adhesion. Methods and Results: We have identified six patients with a subepithelial bullous disorder of mucous membranes and skin who have IgG anti-basement membrane autoantibodies that immunoprecipitate epiligrin from human keratinocyte extracts and culture media. These patients' IgG autoantibodies also bind epiligrin in human keratinocyte extracellular matrix and epidermal basement membrane as determined by immunofluorescence and immunoelectron microscopy. Studies of 10 patients who are clinically indistinguishable from subjects with antiepiligrin autoantibodies (ie, cicatricial pemphigoid pa- tients) found that while seven had anti-basement membrane autoantibodies, the latter are directed exclusively against a region of epidermal basement membrane that does not contain epiligrin, are present in low titer (ie, ≤1:10), do not react with keratinocyte extracellular matrix, and do not bind epiligrin (or any other specific antigen) in immunoprecipitation studies of human keratinocyte extracts or media. Antiepiligrin autoantibodies were also not detected in studies of 36 additional patients with bullous diseases or six normal volunteers. Conclusions: Cicatricial pemphigoid is a disease phenotype in which patients' autoantibodies may target different constituents of epidermal basement membrane. Antiepiligrin autoantibodies are a specific immunologic marker for a group of patients with a disease entity that we propose to designate antiepiligrin cicatricial pemphigoid. (Arch Dermatol. 1994;130:1521-1529)
Part IIThe Nature and Causes of DAS

In a previous letter to the parent(s) of children with developmental apraxia of speech (DAS), the speech characteristics often exhibited as part of the disorder were described. In this second letter, the issues involved in current thinking about the nature of the disorder are explored. Also shared is information concerning what is thought to be known about the causes of the disorder. An appendix of publications exploring these issues appears at the end of the letter.
Inflation in the Einstein-Cartan cosmological model

All the three primordial phases of the universe, required by inflation, plus what is believed to be the present phase, have been studied in the Einstein-Cartan cosmological model in a Bianchi type I metric.
Marketing strategy: discerning the relative influence of product and firm characteristics

A business’s marketing strategy decisions (how a business chooses to compete in the marketplace) are informed by the characteristics of the firm, the product offering, the target customers, the industry, and macro environment, among other factors. The literature in marketing focusing on the marketing strategy implications of product characteristics and customer characteristics is vast and extensive, spanning several decades. During the past four decades, literature insights from the fields of economics and management have contributed to enhancing our understanding of the marketing strategy implications of industry characteristics and firm characteristics, respectively. While the marketing strategy implications of product characteristics generalize to all competitors of a specific product offering, the marketing strategy implications of firm characteristics are idiosyncratic to individual competitors. Competing businesses strive to achieve and sustain defensible competitive positional advantages in the marketplace by effectively leveraging their organizational capabilities to deploy firm resources that are valuable, rare, inimitable, and/or non-substitutable. In effect, heterogeneity in resources and capabilities manifest as heterogeneity in the business and marketing strategies of competitors. A likely consequence of heterogeneity in organizational capabilities is differences among competitors in their quality of understanding the marketing strategy implications of product characteristics and, in turn, their marketing strategies informed by the distinctive characteristics of the product offering. Against this backdrop, this article explores the relative influence of product characteristics and firm characteristics on a business’s marketing strategy and the moderating effect of firm characteristics.
A survey of homeobox genes in Chaetopterus variopedatus and analysis of polychaete homeodomains

A survey of genomic DNA from the polychaete Chaetopterus variopedatus was conducted using the polymerase chain reaction. Twelve unique homeobox-containing gene fragments were recovered. Phylogenetic analysis indicates that seven of the fragments are from genes belonging to Hox homeobox classes. Other fragments show orthology with Xlox, caudal, and Prh homeobox classes, with two fragments not definitely assignable to a homeobox class by our analysis. Orthology with gene sequences reported for the polychaete Ctenodrilus serratus, by Dick and Buss (1994), was calculated and indicated that at least eight of the C. variopedatus fragments are homologous to these previously reported sequences. Tabulation of the Hox gene relationships suggest that polychaetes have representative genes of each of the Hox cognate groups except Abd-B. This conclusion further suggests that the Hox cluster in the basal protostome ancestor had already undergone the gene duplications leading to the complete complement of homeotic genes known in Drosophila, with the possible loss of Abd-B in the polychaete lineage.
Resolution of cyclopentanol methylene proton signals with Eu(fod)3

Abstract Complete resolution of the five different protons of cyclopentanol has been achieved with the use of the lanthanide shift reagent Eu(fod) 3 for the first time, which permits stereochemical differentiation of the cis - and trans -2,5- and 3,4-protons for mechanistic studies of elimination, solvolytic, and other reactions of the cyclopentyl system. The separated peaks are assigned (in order of increasing downfield shift) as: H 3 - and H 4 - trans , H 2 - and H 5 -trans, H 3 - and H 4 - cis , H 2 - and H 5 - cis , and H 1 . An example of application of the technique to mechanistic study is presented in the formolysis of deuterated cyclopentanol.
Blood pressure regulation XI: overview and future research directions.

While the importance of regulating arterial blood pressure within a ‘normal’ range is widely appreciated, the definition of ‘normal’ and the means by which humans and other species regulate blood pressure under various conditions remain hotly debated. The effects of diverse physiological, pathological and environmental challenges on blood pressure and the mechanisms that attempt to maintain it at an optimal level are reviewed and critically analyzed in a series of articles published in this themed issue of the European Journal of Applied Physiology. We summarize here the major points made in these reviews, with emphasis on unifying concepts of regulatory mechanisms and future directions for research.
D. H. MELLOR The Matter of Chance

Though forty years have elapsed since its first publication, it is a testament to the philosophical acumen of its author that The Matter of Chance contains much that is of continued interest to the philosopher of science. Mellor advances a sophisticated propensity theory of chance, arguing that this theory makes better sense than its rivals (in particular subjectivist, frequentist, logical and classical theories) of ‘what professional usage shows to be thought true of chance’ (p. xi)—in particular, ‘that chance is objective, empirical and not relational, and that it applies to the single case’ (ibid.). The book is short and dense, with the serious philosophical content delivered thick and fast. There is little by way of road-mapping or summarizing to assist the reader: the introduction is hardly expansive and the concluding paragraph positively perfunctory. The result is that the book is often difficult going, and the reader is made to work hard to ensure correct understanding of the views expressed. On the other hand, the author’s avoidance of unnecessary use of formalism and jargon ensures that the book is still reasonably accessible. In the following, I shall first summarize the key features of Mellor’s propensity theory, and then offer a few critical remarks.
RGS13 Acts as a Nuclear Repressor of CREB

Cyclic AMP-induced phosphorylation of the transcription factor CREB elicits expression of genes mediating diverse biological functions. In lymphoid organs, the neurotransmitter norepinephrine stimulates beta(2)-adrenergic receptors on B lymphocytes to promote CREB-dependent expression of genes like the B cell Oct 2 coactivator (OCA-B). Although CREB phosphorylation recruits cofactors such as CBP/p300 to stimulate transcription, bona fide endogenous inhibitors of CREB-coactivator or CREB-DNA interactions have not emerged. Here, we identified RGS13, a member of the Regulator of G protein Signaling (RGS) protein family, as a nuclear factor that suppresses CREB-mediated gene expression. cAMP or Ca(2+) signaling promoted RGS13 accumulation in the nucleus, where it formed a complex with phosphorylated CREB and CBP/p300. RGS13 reduced the apparent affinity of pCREB for both the CRE and CBP. B lymphocytes from Rgs13(-/-) mice had more beta(2)-agonist-induced OCA-B expression. Thus, RGS13 inhibits CREB-dependent transcription of target genes through disruption of complexes formed at the promoter.
1-aminobenzotriazole (ABT), the cytochrome P450 suicide inhibitor, sensitizes rats to zymosan induced-multiple organ failure ♦ 184

1-aminobenzotriazole (ABT), the cytochrome P450 suicide inhibitor, sensitizes rats to zymosan induced-multiple organ failure ♦ 184
On the classification of Hilbert Modular threefolds.

Letk be a totally real number field with ring of integersO k . The Hilbert modular variety overk is a desingularization of the (natural) compactification of PSL2(O k )∖H k . The purpose of this paper is to present specific numerical bounds on the size of the discriminantd k of a cubic fieldk with Hilbert modular variety of particular classifications. specifically, it is shown that ifd k>2.12×107, then the Hilbert modular variety overk is not rational and further, ifd k>2.77×108, then Hilbert modular variety overk is of general type.
Noninvasive assessment of asthma severity using pulse oximeter plethysmograph estimate of pulsus paradoxus physiology

Background Pulsus paradoxus estimated by dynamic change in area under the oximeter plethysmograph waveform (PEP) might provide a measure of acute asthma severity. Our primary objective was to determine how well PEP correlates with forced expiratory volume in 1-second (%FEV1) (criterion validity) and change of %FEV1 (responsiveness) during treatment in pediatric patients with acute asthma exacerbations.
Requirement of Phosphatidylinositol 3-Kinase Activity for Bradykinin Stimulation of NF-κB Activation in Cultured Human Epithelial Cells

The signaling mechanisms utilized by bradykinin (BK) to activate the transcription factor nuclear factor κB (NF-κB) are poorly defined. We previously demonstrated that BK-stimulated NF-κB activation requires the small GTPase RhoA. We present evidence that BK-induced NF-κB activation both activates and requires phosphatidylinositol 3-kinase (PI 3-kinase) in A549 human epithelial cells. Pre-treatment with the PI 3-kinase-specific inhibitors, wortmannin, and LY294002 effectively blocked BK-induced PI 3-kinase activity. Wortmannin and LY294002 also abolished BK-induced NF-κB activation, as did transient transfection with a dominant negative mutant of the p85 subunit. BK-stimulated PI 3-kinase activity and NF-κB activation were sensitive to pertussis but not cholera toxin, suggesting that the B2 BK receptors transducing the response were coupled to Gαi or Gαo heterotrimeric G proteins. Tumor necrosis factor α (TNFα) also stimulated increased PI 3-kinase activity, however TNFα-stimulated NF-κB activation was not affected by the PI 3-kinase inhibitors or the p85 dominant negative mutant. These findings provide evidence that BK-induced NF-κB activation utilizes a signaling pathway that requires activity of both RhoA and PI 3-kinase and is distinct from the signaling pathway utilized by TNFα. Furthermore, we show that the p85 regulatory subunit is required for activation of PI 3-kinase activity by this G protein-coupled receptor.
Regulation of Vascular Smooth Muscle Proliferation by Heparin INHIBITION OF CYCLIN-DEPENDENT KINASE 2 ACTIVITY BY p27kip1

Uncontrolled proliferation of vascular smooth muscle cells (VSMCs) contribute to intimal hyperplasia during atherosclerosis and restenosis. Heparin is an antiproliferative agent for VSMCs and has been shown to block VSMC proliferation both in tissue culture systems and in animals. Despite the well documented antiproliferative actions of heparin, its cellular targets largely remain unknown. In an effort to characterize the mechanism of the antiproliferative property of heparin, we have analyzed the effect of heparin on cell cycle in VSMC. Our results indicate that the heparin-induced block in G1 to S phase transition is imposed by p27kip1-mediated inhibition of cyclin-dependent kinase 2 activity. Further analysis of p27kip1 mRNA levels showed that the increase in p27kip1 protein levels in heparin-treated VSMC occurs at posttranscriptional levels. We present evidence that heparin causes stabilization of p27kip1 protein during G1 phase and thereby prevents activation of cyclin-dependent kinase 2.
Wire-guided (Seldinger technique) intubation through a face mask in urgent, difficult and grossly distorted airways

We report two cases of successful urgent intubation using a Seldinger technique for airway management through an anesthesia facemask, while maintaining ventilation in patients with difficult airways and grossly distorted airway anatomy. In both cases, conventional airway management techniques were predicted to be difficult or impossible, and a high likelihood for a surgical airway was present. This technique was chosen as it allows tracheal tube placement through the nares during spontaneous ventilation with the airway stented open and oxygen delivery with either continuous positive airway pressure and/or pressure support ventilation. This unhurried technique may allow intubation when other techniques are unsuitable, while maintaining control of the airway.
Compliance with parental prohibition in autistic children

In a controlled observational study of young autistic children ages 3 to 5, responses to parental prohibition were compared to those of mental-age-matched mentally retarded and normal children. The children were prohibited from eating a candy offered to them by the experimenter. Behavioral response, affect, and gaze patterns were compared across the three groups. Autistic children exhibited significantly less compliant behavior than did children in the two control groups; this behavior correlated with chronological age, not with mental age, language development, or parental behavior. Although affect and gaze patterns of the autistic children were different from the controls, these patterns were not correlated with compliant behavior. In conclusion, when compared to mental-age-matched control groups, autistic children are significantly less compliant to parental prohibition and they show different gaze and affect patterns.
CELL POPULATION KINETICS IN CALLUS TISSUES OF CULTURED PEA ROOT SEGMENTS

A B S T R A C T Two callus tissues, one composed of diploid and the other of a mixture of diploid and polyploid cells, were derived by culturing 1-mm pea root segments; the mixed callus tissues were obtained by incorporation of kinetin in the culture medium. The callus tissues were used to determine (a) if cell proliferation was altered with the change in cell constituents of a callus; (b) the rate at which polyploid cells increased after kinetin stimulation; (c) the nature of the mitotic cycle in the diploid and mixed polyploid callus tissues; and (d) if the mitotic cycle changed as the tissue aged. Histological, cytological, radioisotope, and radioautographic analyses were made on callus tissue ranging from 1 to 4 days old. The results indicated that gross morphological changes were associated with the anatomical location of the proliferative cells. They showed that the percentage of polyploid division figures after stimulation by kinetin increased rapidly during the first 6 to 7 days in culture and then continued to increase at a much reduced rate. Cell counts revealed that cell proliferation in the mixed callus tissue was initially delayed when compared with the diploid tissue, but that after the delay was overcome cell number increased in each in similar manner. Analysis of the number of DNA-synthesizing cells showed that their percentage was highest during the first 2 days of culture and then leveled off at a value of about 10%. Mitotic cycle analysis indicated that it could be accurately measured only in the younger diploid callus tissues and that
Sacral ectopic phallus in a case of extreme penoscrotal transposition and bladder agenesis

This is the first report of a surviving male patient with several rare anomalies including a sacral ectopic phallus, extreme penoscrotal transposition, solitary duplex kidney, and bladder agenesis.