tbuckley/cabot-search huggingface dataset:
STUDIES ON THE MECHANISM OF THE FORMATION OF THE PENICILLIN ANTIGEN
Authors: Bernard B. Levine, Zoltan Ovary
Journal: The Journal of Experimental Medicine (1961)

An excess of D-benzylpenicillenic acid (BPE) was reacted with human gamma-globulin, human serum albumin, gelatin, and poly-L-lysine in aqueous solution buffered at pH 7.5-8.0. Under these conditions, BPE reacted predominantly with lysine epsilon-amino groups of the proteins to form the mixture of diastereomers of epsilon-N-(D-alpha-benzylpenicilloyl)-lysine groups (Di-BPO-Lys). BPE reacted also, but to a considerably smaller extent, with cystine disulfide linkages of human gamma-globulin and human serum albumin to form D-benzylpenicillenic acid-cysteine mixed disulfide groups (BPE-SS-Cys). Conjugates containing large numbers of BPE or D-penicillamine mixed disulfide groups were prepared by reaction of BPE or D-penicillamine with thiolated human gamma-globulin under mild oxidizing conditions. Anti-penicillin antibodies were produced in rabbits by immunization with either potassium penicillin G (PG) or a preincubated mixture of PG with normal rabbit serum (PG-NRS) in complete Freund's adjuvant. Specific precipitation analyses in aqueous and gel media (Ouchterlony), PCA analyses, and specific inhibition of these reactions with haptens were carried out on the rabbit anti-PG and anti-(PG-NRS) sera, using the above conjugates as antigens. The anti-penicillin antibodies were found to be directed against the diastereomeric mixture of N-(D-alpha-benzylpenicilloyl) groups, predominantly the Di-BPO-Lys groups. By these techniques, no antibodies directed against the BPE-mixed disulfide or the D-penicillamine mixed disulfide groups were detected. Three out of six patients with histories of allergic reactions to PG responded with wheal-and-erythema reactions to the N-(D-alpha-benzylpenicilloyl) (BPO) groups contained in BPE-human gamma globulin conjugate. Another such patient exhibited serum antibodies specific for the BPO group. One patient being treated with 25 gm per day of PG showed the presence of non-dialyzable antigenic BPO-conjugates in his serum. These results demonstrate that the diastereomeric BPO groups (predominantly Di-BPO-Lys groups) are major antigenic determinant groups responsible for PG hypersensitivity in rabbits and human beings. The possible clinical usefulness of multivalent Di-BPO conjugates and univalent Di-BPO haptens is discussed.
How we know our own minds: The relationship between mindreading and metacognition
Authors: Peter Carruthers
Journal: Behavioral and Brain Sciences (2009)

Four different accounts of the relationship between third-person mindreading and first-person metacognition are compared and evaluated. While three of them endorse the existence of introspection for propositional attitudes, the fourth (defended here) claims that our knowledge of our own attitudes results from turning our mindreading capacities upon ourselves. Section 1 of this target article introduces the four accounts. Section 2 develops the "mindreading is prior" model in more detail, showing how it predicts introspection for perceptual and quasi-perceptual (e.g., imagistic) mental events while claiming that metacognitive access to our own attitudes always results from swift unconscious self-interpretation. This section also considers the model's relationship to the expression of attitudes in speech. Section 3 argues that the commonsense belief in the existence of introspection should be given no weight. Section 4 argues briefly that data from childhood development are of no help in resolving this debate. Section 5 considers the evolutionary claims to which the different accounts are committed, and argues that the three introspective views make predictions that are not borne out by the data. Section 6 examines the extensive evidence that people often confabulate when self-attributing attitudes. Section 7 considers "two systems" accounts of human thinking and reasoning, arguing that although there are introspectable events within System 2, there are no introspectable attitudes. Section 8 examines alleged evidence of "unsymbolized thinking". Section 9 considers the claim that schizophrenia exhibits a dissociation between mindreading and metacognition. Finally, section 10 evaluates the claim that autism presents a dissociation in the opposite direction, of metacognition without mindreading.
Perinatal and early childhood risk factors associated with rheumatoid factor positivity in a healthy paediatric population
Authors: K. A Young, L. A Parrish, G. O Zerbe, M. Rewers, K. D Deane, V Michael Holers, J. M Norris
Journal: Annals of the Rheumatic Diseases (2006)

To examine perinatal and childhood risk factors for the presence of rheumatoid factor in healthy children.The Diabetes Autoimmunity Study in the Young (DAISY) is a longitudinal study of children at increased risk of type 1 diabetes, based on possession of human leucocyte antigen (HLA)-DR4 and DR3 alleles or a family history of diabetes. 651 children who participated in DAISY, with an average age of 6.4 (range 1-15) years, were tested for the presence of rheumatoid factor in their most recent serum sample. 23 children were positive for rheumatoid factor. Exposure data were collected prospectively by interview. HLA-DR4 alleles were identified using polymerase chain reaction-based Class II genotyping.While exploring risk factors for rheumatoid factor positivity in a multivariate model, several important interaction terms involving HLA-DR4 status suggested the need to evaluate risk factors in HLA-DR4-positive and HLA-DR4-negative children separately. In HLA-DR4-negative children, rheumatoid factor-positive infants were less likely to have been breast fed for >3 months (odds ratio (OR) 0.18; 95% confidence interval (CI) 0.04 to 0.99), more likely to have been exposed to non-parental tobacco smoke (OR 5.38; 95% CI 0.93 to 31.27) and more likely to be a race/ethnicity other than non-Hispanic white (OR 6.94; 95% CI 1.10 to 43.88) compared with rheumatoid factor-negative children, after adjusting for age, sex and maternal education. In HLA-DR4-positive children, there were no significantly associated risk factors for rheumatoid factor positivity.Risk factors for rheumatoid factor positivity in children vary by HLA-DR4 genotype. In HLA-DR4-negative children, breast feeding may decrease the risk, and environmental tobacco smoke may increase the risk, of autoimmunity.
Indel-Associated Mutation Rate Varies with Mating System in Flowering Plants
Authors: J. D. Hollister, J. Ross-Ibarra, B. S. Gaut
Journal: Molecular Biology and Evolution (2009)

A recently proposed mutational mechanism, indel-associated mutation (IDAM), posits that heterozygous insertions/deletions (indels) increase the point mutation rate at nearby nucleotides due to errors during meiosis. This mechanism could have especially dynamic consequences for the evolution of plant genomes, because the high degree of variation in the rate of self-fertilization among plant species causes differences in the heterozygosity of alleles, including indel alleles, segregating in plant species. In this study, we investigated the consequences of IDAM for species differing in mating system using both forward population genetic simulations and genomewide DNA resequencing data from Arabidopsis thaliana, Oryza sativa, and Oryza rufipogon. Simulations of different levels of selfing suggest that the effect of IDAM on surrounding nucleotide diversity should decrease with increasing selfing rate. Further simulations incorporating selfing rates and the time of onset of selfing suggest that the time since the switch to selfing also affects patterns of nucleotide diversity due to IDAM. Population genetic analyses of A. thaliana and Oryza DNA sequence data sets empirically confirmed our simulation results, revealing the strongest effect of IDAM in the outcrossing O. rufipogon, a weaker effect in the recently evolved selfer O. sativa, and the weakest effect in the relatively ancient selfer A. thaliana. These results support the novel idea that differences in life history, such as the level of selfing, can affect the per-individual mutation rate among species.
Decline in NRF2-regulated Antioxidants in Chronic Obstructive Pulmonary Disease Lungs Due to Loss of Its Positive Regulator, DJ-1
Authors: Deepti Malhotra, Rajesh Thimmulappa, Ana Navas-Acien, Andrew Sandford, Mark Elliott, Anju Singh, Linan Chen, Xiaoxi Zhuang, James Hogg, Peter Pare, Rubin M. Tuder, Shyam Biswal
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Oxidative stress is a key contributor in chronic obstructive pulmonary disease (COPD) pathogenesis caused by cigarette smoking. NRF2, a redox-sensitive transcription factor, dissociates from its inhibitor, KEAP1, to induce antioxidant expression that inhibits oxidative stress.To determine the link between severity of COPD, oxidative stress, and NRF2-dependent antioxidant levels in the peripheral lung tissue of patients with COPD.We assessed the expression of NRF2, NRF2-dependent antioxidants, regulators of NRF2 activity, and oxidative damage in non-COPD (smokers and former smokers) and smoker COPD lungs (mild and advanced). Cigarette smoke-exposed human lung epithelial cells (Beas2B) and mice were used to understand the mechanisms.When compared with non-COPD lungs, the COPD patient lungs showed (1) marked decline in NRF2-dependent antioxidants and glutathione levels, (2) increased oxidative stress markers, (3) significant decrease in NRF2 protein with no change in NRF2 mRNA levels, and (4) similar KEAP1 but significantly decreased DJ-1 levels (a protein that stabilizes NRF2 protein by impairing KEAP1-dependent proteasomal degradation of NRF2). Exposure of Bea2B cells to cigarette smoke caused oxidative modification and enhanced proteasomal degradation of DJ-1 protein. Disruption of DJ-1 in mouse lungs, mouse embryonic fibroblasts, and Beas2B cells lowered NRF2 protein stability and impaired antioxidant induction in response to cigarette smoke. Interestingly, targeting KEAP1 by siRNA or the small-molecule activator sulforaphane restored induction of NRF2-dependent antioxidants in DJ-1-disrupted cells in response to cigarette smoke.NRF2-dependent antioxidants and DJ-1 expression was negatively associated with severity of COPD. Therapy directed toward enhancing NRF2-regulated antioxidants may be a novel strategy for attenuating the effects of oxidative stress in the pathogenesis of COPD.
ON THE DIFFERENCES IN THE EFFECTS OF STIMULATION OF THE TWO VAGUS NERVES ON RATE AND CONDUCTION OF THE DOG'S HEART
Authors: Alfred E. Cohn
Journal: The Journal of Experimental Medicine (1912)

It may be concluded from the results obtained in these experiments : 1. That stimulation of the right vagus nerve in the dog usually causes arrest of all the chambers of the heart. 2. That stimulation of the left vagus nerve exerts a moderate negative chronotropic effect on the auricles. 3. That stimulation of the left vagus nerve has a profound effect on the conduction of impulses over the auriculoventricular system. 4. That the degree of effect exercised on the auriculoventricular system by stimulation of the left vagus nerve varies. In some dogs conduction is depressed to an extent which causes only a delay in the conduction of impulses from auricles to ventricles (P-R time) ; in other dogs the conduction is depressed to a degree which results in incomplete heart-block; while in still other dogs conduction is so depressed that although the auricles continue to contract, no impulses pass from them to the ventricles. 5. That when stimulation of either the right or left vagus nerve causes asystole of nomotopic ventricular contractions, ectopic ventricular contractions may occur. 6. That the time which elapses before ectopic ventricular contractions occur depends upon the irritability of the ventricular muscle, and this may vary in different dogs. 7. That stimulation of the left vagus nerve may rarely cause sino-auricular block. Possibly stimulation of the right nerve may also produce this effect. 8. That there is consequently usually a great qualitative difference in the action of the two vagus nerves on the heart of the dog.
Immunologic properties of bacterial lipopolysaccharide (LPS). III. Genetic linkage between the in vitro mitogenic and in vivo adjuvant properties of LPS.
Authors: B J Skidmore, J M Chiller, W O Weigle, R Riblet, J Watson
Journal: The Journal of Experimental Medicine (1976)

The mechanism was investigated underlying the activity of bacterial lipopolysaccharide (LPS) as an adjuvant of antibody formation as assessed by its capacity to modulate the induction of tolerance in mice to the antigen human Ig G (HGG) into a state of immunity to HGG. The adjuvant activity of LPS was found to be closely correlated with its ability to function as a B-cell mitogen. This correlation was revealed by an analysis of the genetic control of the mitogenic and adjuvant properties of LPS utilizing the refractory state inherent in the C3H/HeJ mouse strain to these activities of LPS. Thus, mice that were the progeny of a backcross between the nonresponder C3H/JeJ parent and the responder (C3H/HeJ X CWB) F1 hybrid were individually typed for responsiveness to LPS, as an adjuvant and as a B-cell mitogen. It was found that LPS interfered with tolerance induction to HGG in vivo only in those backcross progeny whose spleen cells were also capable of responding mitogenically to LPS in vitro, demonstrating that the adjuvant and B-cell mitogenic properties of LPS are genetically linked. In contrast, these properties were observed to segregate independently from either H-2 or heavy chain allotype loci, and were not sex linked. These results are compatible with the concepts that, in this system, (a) the cellular site of action of LPS as an adjuvant is confined to B cells, and (b) the subcellular mode of action of LPS as an adjuvant may involve the delivery of a "signal" to B cells which is a stimulus for mitogenesis.
Graft Permeabilization Facilitates Gene Therapy of Transplant Arteriosclerosis in a Rabbit Model
Authors: Mark D. Rekhter, Nikhil Shah, Robert D. Simari, Carolyn Work, Jong-Seung Kim, Gary J. Nabel, Elizabeth G. Nabel, David Gordon
Journal: Circulation (1998)

Background —Smooth muscle cell (SMC) replication plays a central role in the pathogenesis of transplant arteriosclerosis. One strategy to eliminate dividing cells is to express a herpesvirus thymidine kinase ( tk ) gene that phosphorylates the nucleoside analogue ganciclovir into a toxic form leading to cell killing. However, medial SMCs are resistant to gene transfer unless the artery undergoes deendothelialization. We hypothesized that manipulations that increase the “porosity” of the artery can make SMCs prone to gene transfer without denudation. Methods and Results —In organ culture of rabbit aorta, longitudinal stretch and supraphysiological pressure applied for 3 hours during incubation with adenoviral vector facilitated gene transfer into medial SMCs without denudation. Of the SMCs, 10.2±3.8% expressed a reporter gene of human placental alkaline phosphatase (hpAP), whereas SMCs in control arteries did not express hpAP. To evaluate the feasibility of transgene expression in arterial grafts, we performed such permeabilization-assisted reporter gene transfer into aortas of donor Dutch Belted rabbits and transplanted them into carotid arteries of recipient New Zealand White rabbits. Unstretched transfected grafts were used as a control. SMCs expressed hpAP (7.3±2.4% of cells in 2 days and 4.2±1.9% in 2 weeks) in stretched grafts only. In the next series of experiments, we transfected stretched grafts with ADV- tk and combined transplantation with systemic administration of ganciclovir. Stretched ADV-hpAP grafts were used as a control. In 2 weeks, the formation of intimal thickening in tk -expressing grafts was significantly reduced ( P &lt;0.01) because of a decrease in proliferating SMCs. Conclusions —Manipulations within target tissues can enhance the efficiency of gene transfer into SMCs. Although mechanical permeabilization is clinically problematic, in principle, targeting SMC replication may provide a genetic approach to the treatment of transplant arteriosclerosis.
A "waiting for investigation" index would be useful
Authors: V. Pope
Journal: BMJ (2002)

EDITOR—Oliver raises the point that all stages of the cancer care pathway need speeding up, not just the time taken to see urgent referrals under the two week rule.1 We are becoming increasingly concerned about the long delays that many patients experience while they wait for investigations needed before the most appropriate treatment can be decided.

The initial delay to see a hospital consultant, and the time spent on a waiting list …
Respiratory symptoms and dust exposure in Lancashire cotton and man-made fiber mill operatives.
Authors: D Fishwick, A M Fletcher, C A Pickering, R M Niven, E B Faragher
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

A cross-sectional study of work-related symptoms and cotton dust exposure was made in 404 man-made fiber and 1,048 cotton operatives in Lancashire spinning mills; 39 cotton-exposed operatives (3.7%) had symptoms of byssinosis. This was associated on regression analysis with cumulative lifetime cotton dust exposure (p < 0.001), total years spent carding (p < 0.001), and currently working in the carding area (p = 0.0041). Smoking habit did not differ significantly between byssinotic and nonbyssinotic workers. Other work-related symptoms were common: chronic bronchitis (CB) and persistent cough. The prevalence of CB correlated positively with dust exposure (r = 0.59). Cotton dust sampling was performed in the work area (SDPRES) and personal breathing zone (PD1). A retrospective estimate of lifetime cotton dust exposure based on SDPRES correlated best with the prevalence of byssinosis (r = 0.797), although correlations with PD1 (r = 0.709) and SDPRES (r = 0.594) were also significant.
Mutations in LRRK2 potentiate age-related impairment of autophagic flux
Authors: Shamol Saha, Peter E. A. Ash, Vivek Gowda, Liqun Liu, Orian Shirihai, Benjamin Wolozin
Journal: Molecular Neurodegeneration (2015)

Autophagy is thought to play a pivotal role in the pathophysiology of Parkinson's disease, but little is known about how genes linked to PD affect autophagy in the context of aging. We generated lines of C. elegans expressing reporters for the autophagosome and lysosome expressed only in dopaminergic neurons, and examined autophagy throughout the lifespan in nematode lines expressing LRRK2 and α-synuclein. Dopamine neurons exhibit a progressive loss of autophagic function with aging. G2019S LRRK2 inhibited autophagy and accelerated the age-related loss of autophagic function, while WT LRRK2 improved autophagy throughout the life-span. Expressing α-synuclein with G2019S or WT LRRK2 caused age-related synergistic inhibition of autophagy and increase in degeneration of dopaminergic neurons. The presence of α-synuclein particularly accentuated age-related inhibition of autophagy by G2019S LRRK2. This work indicates that LRRK2 exhibits a selective, age-linked deleterious interaction with α-synuclein that promotes neurodegeneration.
Enhanced Susceptibility of Irradiated Tumor Vessels to Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibition
Authors: Daniel Zips, Wolfgang Eicheler, Peter Geyer, Franziska Hessel, Annegret Dörfler, Howard D. Thames, Martin Haberey, Michael Baumann
Journal: Cancer Research (2005)

Abstract Previous experiments with PTK787/ZK222584, a specific inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, using irradiated human FaDu squamous cell carcinoma in nude mice, suggested that radiation-damaged tumor vessels are more sensitive to VEGFR inhibition. To test this hypothesis, the tumor transplantation site (i.e., the right hind leg of nude mice) was irradiated 10 days before transplantation of FaDu to induce radiation damage in the host tissue. FaDu tumors vascularized by radiation-damaged blood vessels appeared later, grew at a slower rate, and showed more necrosis and a smaller vessel area per central tumor section than controls. PTK787/ZK222584 at a daily dose of 50 mg/kg body weight had no impact on growth of control tumors. In contrast, tumors vascularized by radiation-damaged vessels responded to PTK787/ZK222584 with longer latency and slower growth rate than controls, and a trend toward further increase in necrosis, indicating that irradiated tumor vessels are more susceptible to VEGFR inhibition than unirradiated vessels. Although not proving causality, expression analysis of VEGF and VEGFR2 shows that enhanced sensitivity of irradiated vessels to a specific inhibitor of VEGFR tyrosine kinases correlates with increased expression of the molecular target.
Bisbenzamidine derivative, pentamidine represses DNA damage response through inhibition of histone H2A acetylation
Authors: Junya Kobayashi, Akihiro Kato, Yosuke Ota, Reiko Ohba, Kenshi Komatsu
Journal: Molecular Cancer (2010)

MRE11 is an important nuclease which functions in the end-resection step of homologous recombination (HR) repair of DNA double-strand breaks (DSBs). As MRE11-deficient ATLD cells exhibit hyper radio-sensitivity and impaired DSB repair, MRE11 inhibitors could possibly function as potent radio-sensitizers. Therefore, we investigated whether a bisbenzamidine derivative, pentamidine, which can inhibit endoexonuclease activity, might influence DSB-induced damage responses via inhibition of MRE11. We first clarified that pentamidine inhibited MRE11 nuclease activity and also reduced ATM kinase activity in vitro. Pentamidine increased the radio-sensitivity of HeLa cells, suggesting that this compound could possibly influence DNA damage response factors in vivo. Indeed, we found that pentamidine reduced the accumulation of γ-H2AX, NBS1 and phospho-ATM at the sites of DSBs. Furthermore, pentamidine decreased HR activity in vivo. Pentamidine was found to inhibit the acetylation of histone H2A which could contribute both to inhibition of IR-induced focus formation and HR repair. These results suggest that pentamidine might exert its effects by inhibiting histone acetyltransferases. We found that pentamidine repressed the activity of Tip60 acetyltransferase which is known to acetylate histone H2A and that knockdown of Tip60 by siRNA reduced HR activity. These results indicate that inhibition of Tip60 as well as hMRE11 nuclease by pentamidine underlies the radiosensitizing effects of this compound making it an excellent sensitizer for radiotherapy or chemotherapy.
Cardiovascular function and survival during severe systemic hypoxaemia : influence of glucosepotassium-insulin solution and of beta-blockade
Authors: K. WILDENTHAL, J. S. CRIE, G. F. VASTAGH
Journal: Cardiovascular Research (1973)

Journal Article Cardiovascular function and survival during severe systemic hypoxaemia : influence of glucosepotassium-insulin solution and of beta-blockade Get access KERN WILDENTHAL, KERN WILDENTHAL From the Pauline and Adolph Weinberger Laboratory for Cardiopulmonary Research, Depertments of Internal Medicine and Physiology, University of Texas Southwestern Medical School at Dallas, Dallas, Texas 75235 U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar J. STANLEY CRIE, J. STANLEY CRIE From the Pauline and Adolph Weinberger Laboratory for Cardiopulmonary Research, Depertments of Internal Medicine and Physiology, University of Texas Southwestern Medical School at Dallas, Dallas, Texas 75235 U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar GEORGE F. VASTAGH GEORGE F. VASTAGH From the Pauline and Adolph Weinberger Laboratory for Cardiopulmonary Research, Depertments of Internal Medicine and Physiology, University of Texas Southwestern Medical School at Dallas, Dallas, Texas 75235 U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 7, Issue 2, March 1973, Pages 174–180, https://doi.org/10.1093/cvr/7.2.174 Published: 01 March 1973